Bicycloheteroarylamine compounds as ion channel ligands and uses thereof

ABSTRACT

Amine compounds are disclosed that have a formula represented by the following: 
                         
The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.

CROSS REFERENCE TO RELATED APPLICATION

The present application claims the priority of provisional applicationU.S. Ser. No. 60/532,371, filed on Dec. 24, 2003. The disclosure of thisapplication is incorporated by reference herein in its entirety.Applicants claim the benefits of this application under 35 U.S.C.§119(e).

FIELD OF THE INVENTION

This invention relates to novel amine compounds of the classtetrahydronaphthyridines and to pharmaceutical compositions containingsuch compounds. This invention also relates to methods for preventingand/or treating inflammation-related conditions in mammals, such as (butnot limited to) arthritis, Parkinson's disease, Alzheimer's disease,stroke, uveitis, asthma, myocardial infarction, the treatment andprophylaxis of pain syndromes (acute and chronic or neuropathic),traumatic brain injury, acute spinal cord injury, neurodegenerativedisorders, alopecia (hair loss), inflammatory bowel disease andautoimmune disorders, using the amine compounds and pharmaceuticalcompositions of the invention.

BACKGROUND OF THE INVENTION

Studies of signaling pathways in the body have revealed the existence ofion channels and sought to explain their role. Ion channels are integralmembrane proteins with two distinctive characteristics: they are gated(open and closed) by specific signals such as membrane voltage or thedirect binding of chemical ligands and, once open, they conduct ionsacross the cell membrane at very high rates.

There are many types of ion channels. Based on their selectivity toions, they can be divided into calcium channel, potassium channel,sodium channel, etc. The calcium channel is more permeable to calciumions than other types of ions, the potassium channel selects potassiumions over other ions, and so forth. Ion channels may also be classifiedaccording to their gating mechanisms. In a voltage-gated ion channel,the opening probability depends on the membrane voltage, whereas in aligand-gated ion channel, the opening probability is regulated by thebinding of small molecules (the ligands). Since ligand-gated ionchannels receive signals from the ligand, they may also be considered as“receptors” for ligands.

Examples of ligand-gated ion channels include nAChR (nicotinicacetylcholine receptor) channel, GluR (glutamate receptor) channel,ATP-sensitive potassium channel, G-protein activated channel,cyclic-nucleotide-gated channel, etc.

Transient receptor potential (TRP) channel proteins constitute a largeand diverse family of proteins that are expressed in many tissues andcell types. This family of channels mediates responses to nerve growthfactors, pheromones, olfaction, tone of blood vessels and metabolicstress et al., and the channels are found in a variety of organisms,tissues and cell types including nonekcitable, smooth muscle andneuronal cells. Furthermore, TRP-related channel proteins are implicatedin several diseases, such as several tumors and neurodegenerativedisorders and the like. See, for example, Minke, et al., APStracts9:0006P (2002).

Nociceptors are specialized primary afferent neurons and the first cellsin a series of neurons that lead to the sensation of pain. The receptorsin these cells can be activated by different noxious chemical orphysical stimuli. The essential functions of nociceptors include thetransduction of noxious stimuli into depolarizations that trigger actionpotentials, conduction of action potentials from primary sensory sitesto synapses in the central nervous system, and conversion of actionpotentials into neurotransmitter release at presynaptic terminals, allof which depend on ion channels.

One TRP channel protein of particular interest is the vanilloidreceptor. Also known as VR1, the vanilloid receptor is a non-selectivecation channel which is activated or sensitized by a series of differentstimuli including capsaicin, heat and acid stimulation and products oflipid bilayer metabolism (anandamide), and lipoxygenase metabolites.See, for example Smith, et al., Nature, 418:186-190 (2002). VR1 does notdiscriminate among monovalent cations, however, it exhibits a notablepreference for divalent cations with a permeability sequence ofCa²⁺>Mg²⁺>Na⁺═K⁺═Cs⁺. Ca²⁺ is especially important to VR1 function, asextracellular Ca²⁺ mediates desensitization, a process which enables aneuron to adapt to specific stimuli by diminishing its overall responseto a particular chemical or physical signal. VR1 is highly expressed inprimary sensory neurons in rats, mice and humans, and innervates manyvisceral organs including the dermis, bones, bladder, gastrointestinaltract and lungs. It is also expressed in other neuronal and non-neuronaltissues including the CNS, nuclei, kidney, stomach and T-cells. The VR1channel is a member of the superfamily of ion channels with sixmembrane-spanning domains, with highest homology to the TRP family ofion channels.

VR1 gene knockout mice have been shown to have reduced sensorysensitivity to thermal and acid stimuli. See, for example, Caterina, etal. Science, 14:306-313 (2000). This supports the concept that VR1contributes not only to generation of pain responses but also to themaintenance of basal activity of sensory nerves. VR1 agonists andantagonists have use as analgesics for the treatment of pain of variousgenesis or etiology, for example acute, inflammatory and neuropathicpain, dental pain and headache (such as migraine, cluster headache andtension headache). They are also useful as anti-inflammatory agents forthe treatment of arthritis, Parkinson's Disease, Alzheimer's Disease,stroke, uveitis, asthma, myocardial infarction, the treatment andprophylaxis of pain syndromes (acute and chronic [neuropathic]),traumatic brain injury, spinal cord injury, neurodegenerative disorders,alopecia (hair loss), inflammatory bowel disease and autoimmunedisorders, renal disorders, obesity, eating disorders, cancer,schizophrenia, epilepsy, sleeping disorders, cognition, depression,anxiety, blood pressure, lipid disorders, and atherosclerosis.

Compounds, such as those of the present invention, which interact withthe vanilloid receptor can thus play a role in treating or preventing orameliorating these conditions.

A wide variety of Vanilloid compounds of different structures are knownin the art, for example those disclosed in European Patent ApplicationNumbers, EP 0 347 000 and EP 0 401 903, UK Patent Application Number GB2226313 and International Patent Application, Publication Number WO92/09285. Particularly notable examples of vanilloid compounds orvanilloid receptor modulators are capsaicin or trans8-methyl-N-vanillyl-6-nonenamide which is isolated from the pepperplant, capsazepine (Tetrahedron, 53, 1997, 4791) and olvanil or-N-(4-hydroxy-3-methoxybenzyl)oleamide (J. Med. Chem., 36, 1993, 2595).

International Patent Application, Publication Number WO 02/08221discloses diaryl piperazine and related compounds which bind with highselectivity and high affinity to vanilloid receptors, especially Type IVanilloid receptors, also known as capsaicin or VR1 receptors. Thecompounds are said to be useful in the treatment of chronic and acutepain conditions, itch and urinary incontinence.

International Patent Application, Publication Numbers WO 02/16317, WO02/16318 and WO 02/16319 suggest that compounds having a high affinityfor the vanilloid receptor are useful for treating stomach-duodenalulcers.

WO02/053558 describes certain quinazolone derivatives as alpha 1A/Badrenergic receptor antagonists, and WO03/076427 and WO04/041259 bothdescribe compounds of the same class for use in the treatment of femalesexual dysfunction. WO04/56774 describe certain substitutedbiphenyl-4-carboxylic acid arylamide analogues having possibleapplication as receptor modulators. Also, WO03/104230 describes certainbicyclic pyrimidine derivatives, and U.S. Published application Ser. No.20030092908 and WO02/087513 describe fused heterocyclic PDE7 inhibitors.

U.S. Pat. Nos. 3,424,760 and 3,424,761 both describe a series of3-Ureidopyrrolidines that are said to exhibit analgesic, central nervoussystem, and pyschopharmacologic activities. These patents specificallydisclose the compounds 1-(1l-phenyl-3-pyrrolidinyl)-3-phenyl urea and1-(1-phenyl-3-pyrrolidinyl)-3-(4-methoxyphenyl)urea respectively.International Patent Applications, Publication Numbers WO 01/62737 andWO 00/69849 disclose a series of pyrazole derivatives which are statedto be useful in the treatment of disorders and diseases associated withthe NPY receptor subtype Y5, such as obesity. WO 01/62737 specificallydiscloses the compound5-amino-N-isoquinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.WO 00/69849 specifically discloses the compounds5-methyl-N-quinolin-8-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide,5-methyl-N-quinolin-7-yl-1-[3-trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide,5-methyl-N-quinolin-3-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide,N-isoquinolin-5-yl-5-methyl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide,5-methyl-N-quinolin-5-yl-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide,1-(3-chlorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide,N-isoquinolin-5-yl-1-(3-methoxyphenyl)-5-methyl-1H-pyrazole-3-carboxamide,1-(3-fuorophenyl)-N-isoquinolin-5-yl-5-methyl-1H-pyrazole-3-carboxamide,1-(2-chloro-5-trifluoromethylphenyl)-N-isoquinolin-5-yl-5-methyl-1N-pyrazole-3-carboxamide,5-methyl-N-(3-methylisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1N-pyrazole-3-carboxamide,5-methyl-N-(1,2,3,4-tetrahydroisoquinolin-5-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazole-3-carboxamide.

German Patent Application Number 2502588 describes a series ofpiperazine derivatives. This application specifically discloses thecompoundN-[3-[2-(diethylamino)ethyl]-1,2-dihydro-4-methyl-2-oxo-7-quinolinyl]-4-phenyl-1-piperazinecarboxamide.

We have now discovered that certain compounds have surprising potencyand selectivity as VR1 antagonists. The compounds of the presentinvention are considered to be particularly beneficial as VR1antagonists as certain compounds exhibit improved aqueous solubility andmetabolic stability.

SUMMARY OF THE INVENTION

It has now been found that tetrahydronaphthyridine compounds are capableof modifying mammalian ion channels such as the VR1 cation channel. Thisfinding leads to novel compounds having therapeutic value. It also leadsto pharmaceutical compositions having the amines of the present invetionas active ingredients and to their use to treat, prevent or ameliorate arange of conditions in mammals such as but not limited to pain ofvarious genesis or etiology, for example acute, chronic, inflammatoryand neuropathic pain, dental pain and headache (such as migraine,cluster headache and tension headache).

The compounds of the present invention are useful for the treatment ofinflammatory pain and associated hyperalgesia and allodynia. They arealso useful for the treatment of neuropathic pain and associatedhyperalgesis and allodynia (e.g. trigeminal or herpetic neuralgia,diabetic neuropathy, causalgia, sympathetically maintained pain anddeafferentation syndromes such as brachial plexus avulsion). Thecompounds of the present invention are also useful as anti-inflammatoryagents for the treatment of arthritis, and as agents to treatParkinson's Disease, Alzheimer's Disease, stroke, uveitis, asthma,myocardial infarction, traumatic brain injury, spinal cord injury,neurodegenerative disorders, alopecia (hair loss), inflammatory boweldisease and autoimmune disorders, renal disorders, obesity, eatingdisorders, cancer, schizophrenia, epilepsy, sleeping disorders,cognition, depression, anxiety, blood pressure, lipid disorders, andatherosclerosis.

In one aspect, this invention provides tetrahydronaphthyridine compoundswhich are capable of modifying ion channels, in vivo. Representative ionchannels so modified include voltage-gated channels and ligand-gatedchannels, including cation channels such as vanilloid channels.

Accordingly, in a first aspect of the invention, amine compounds aredisclosed that are capable of modifying ion channels, in vivo, having aformula (1):

wherein

-   -   A and B are independently selected from CH₂, CR²R⁴, CO, CS, NR¹,        and NR²;    -   Y is independently selected from CH₂, CR²R⁴, NR¹, and NR²;    -   W and Z are independently selected from CR⁴ and N, provided that        W and Z both can not be N;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   R² is selected from hydrogen, substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl,        substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof.

More particularly, there is provided an amine compound capable ofmodifying ion channels, in vivo, having a formula:

wherein

-   -   A and B are independently selected from CH₂, CR^(2′)R^(2′), CO,        CS and NR^(2′);    -   Y is independently selected from CH₂, CR^(2′)R^(2′) and NR^(2′);    -   W and Z are independently selected from CR⁴ and N, provided that        W and Z both can not be N;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   Each of R² and R^(2′) is selected from hydrogen, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆        cycloalkyl, substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof. In a further embodimeny        A, B and Y may all represent CH₂.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising a tetrahydronaphthyridine compound of theinvention, and a pharmaceutical carrier, excipient or diluent. In thisaspect of the invention, the pharmaceutical composition can comprise oneor more of the amine compounds described herein. Moreover, the aminecompounds of the present invention useful in the pharmaceuticalcompositions and treatment methods disclosed herein, are allpharmaceutically acceptable as prepared and used.

In a further aspect of the invention, this invention provides a methodof treating a mammal susceptible to or afflicted with a condition fromamong those listed herein, and particularly, such condition as may beassociated with e.g. arthritis, uveitis, asthma, myocardial infarction,traumatic brain injury, acute spinal cord injury, alopecia (hair loss),inflammatory bowel disease and autoimmune disorders, which methodcomprises administering an effective amount of one or more of thepharmaceutical compositions just described.

In yet another method of treatment aspect, this invention provides amethod of treating a mammal susceptible to or afflicted with a conditionthat gives rise to pain responses or that relates to imbalances in themaintenance of basal activity of sensory nerves. The amine compounds ofthe invention have use as analgesics for the treatment of pain ofvarious geneses or etiology, for example acute, inflammatory pain (suchas pain associated with osteoarthritis and rheumatoid arthritis);various neuropathic pain syndromes (such as post-herpetic neuralgia,trigeminal neuralgia, reflex sympathetic dystrophy, diabetic neuropathy,Guillian Barre syndrome, fibromyalgia, phantom limb pain, post-masectomypain, peripheral neuropathy, HIV neuropathy, and chemotherapy-inducedand other iatrogenic neuropathies); visceral pain, (such as thatassociated with gastroesophageal reflex disease, irritable bowelsyndrome, inflammatory bowel disease, pancreatitis, and variousgynecological and urological disorders), dental pain and headache (suchas migraine, cluster headache and tension headache).

In additional method of treatment aspects, this invention providesmethods of treating a mammal susceptible to or afflicted withneurodegenerative diseases and disorders such as, for exampleParkinson's disease, Alzheimer's disease and multiple sclerosis;diseases and disorders which are mediated by or result inneuroinflammation such as, for example traumatic brain injury, stroke,and encephalitis; centrally-mediated neuropsychiatric diseases anddisorders such as, for example depression mania, bipolar disease,anxiety, schizophrenia, eating disorders, sleep disorders and cognitiondisorders; epilepsy and seizure disorders; prostate, bladder and boweldysfunction such as, for example urinary incontinence, urinaryhesitancy, rectal hypersensitivity, fecal incontinence, benign prostatichypertrophy and inflammatory bowel disease; respiratory and airwaydisease and disorders such as, for example, allergic rhinitis, asthmaand reactive airway disease and chronic obstructive pulmonary disease;diseases and disorders which are mediated by or result in inflammationsuch as, for example rheumatoid arthritis and osteoarthritis, myocardialinfarction, various autoimmune diseases and disorders, uveitis andatherosclerosis; itch/pruritus such as, for example psoriasis; alopecia(hair loss); obesity; lipid disorders; cancer; blood pressure; spinalcord injury; and renal disorders method comprises administering aneffective condition-treating or condition-preventing amount of one ormore of the pharmaceutical compositions just described.

In additional aspects, this invention provides methods for synthesizingthe amine compounds of the invention, with representative syntheticprotocols and pathways disclosed later on herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description whichproceeds with reference to the following illustrative drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: A graph demonstrating the activity of compound 1 in inhibiting acapsaicin induced intracellular calcium current. The graph presents adose response curve developed using electrophysiology.

FIG. 2: A graph demonstrating the activity of compound 1 in inhibitingthermal hyperalgesia, as measured by increased latency of pawwithdrawal. The graph depicts the time interval at which paw withdrawaltakes place, measured at baseline and two hours after stimulation.

DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS

When describing the compounds, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, thefollowing terms have the following meanings unless otherwise indicated.It should also be understood that, consistent with the scope of thepresent invention, any of the moieties defined herein and/or set forthbelow may be substituted with a variety of substituents, and that therespective definitions are intended to include such substituted moietieswithin their scope. By way of non-limiting example, such substituentsmay include e.g. halo (such as fluoro, chloro, bromo), —CN, —CF₃, —OH,—OCF₃, C₂-₆ alkenyl, C₃-₆ alkynyl, C₁-₆ alkoxy, aryl and di-C₁-₆alkylamino.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” refers to a radical —NR′C(O)R, where R′ is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl and R is hydrogen, alkyl, alkoxy, cycloalkyl,cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl orheteroarylalkyl, as defined herein. Representative examples include, butare not limited to, formylamino, acetylamino, cyclohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino andthe like.

“Acyloxy” refers to the group —OC(O)R where R is hydrogen, alkyl, arylor cycloalkyl.

“Substituted alkenyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkenyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkoxy” refers to the group —OR where R is alkyl. Particular alkoxygroups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkoxy group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— andaryl-S(O)₂—.

“Alkoxycarbonylamino” refers to the group —NRC(O)OR′ where R ishydrogen, alkyl, aryl or cycloalkyl, and R′ is alkyl or cycloalkyl.

“Aliphatic” refers to hydrocarbyl organic compounds or groupscharacterized by a straight, branched or cyclic arrangement of theconstituent carbon atoms and an absence of aromatic unsaturation.Aliphatics include, without limitation, alkyl, alkylene, alkenyl,alkenylene, alkynyl and alkynylene. Aliphatic groups typically have from1 or 2 to about 12 carbon atoms.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupsparticularly having up to about 11 carbon atoms, more particularly as alower alkyl, from 1 to 8 carbon atoms and still more particularly, from1 to 6 carbon atoms. The hydrocarbon chain may be eitherstraight-chained or branched. This term is exemplified by groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl,n-hexyl, n-octyl, tert-octyl and the like. The term “lower alkyl” refersto alkyl groups having 1 to 6 carbon atoms. The term “alkyl” alsoincludes “cycloalkyl” as defined below.

“Substituted alkyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkyl group having 1or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂—, andaryl-S(O)₂—.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupsparticularly having up to about 11 carbon atoms and more particularly 1to 6 carbon atoms which can be straight-chained or branched. This termis exemplified by groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—),the propylene isomers (e.g., —CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” includes those groups recited in the definitionof “substituted” herein, and particularly refers to an alkylene grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbylgroups preferably having up to about 11 carbon atoms, particularly, from2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms,which can be straight-chained or branched and having at least 1 andparticularly from 1 to 2 sites of olefinic unsaturation. Particularalkenyl groups include ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂),isopropenyl (—C(CH₃)═CH₂), vinyl and substituted vinyl, and the like.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbylgroups particularly having up to about 11 carbon atoms and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofolefinic unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH═CHCH₂— and—C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to acetylenically unsaturated hydrocarbyl groupsparticularly having up to about 11 carbon atoms and more particularly 2to 6 carbon atoms which can be straight-chained or branched and havingat least 1 and particularly from 1 to 2 sites of alkynyl unsaturation.Particular non-limiting examples of alkynyl groups include acetylenic,ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Substituted alkynyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkynyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkanoyl” as used herein, which can include “acyl”, refers to the groupR—C(O)—, where R is hydrogen or alkyl as defined above.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Particularly, anaryl group comprises from 6 to 14 carbon atoms.

“Substituted Aryl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an aryl group that mayoptionally be substituted with 1 or more substituents, for instance from1 to 5 substituents, particularly 1 to 3 substituents, selected from thegroup consisting of acyl, acylamino, acyloxy, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substitutedalkyl, alkynyl, substituted alkynyl, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring.

“Alkaryl” refers to an aryl group, as defined above, substituted withone or more alkyl groups, as defined above.

“Aralkyl” or “arylalkyl” refers to an alkyl group, as defined above,substituted with one or more aryl groups, as defined above.

“Aryloxy” refers to —O-aryl groups wherein “aryl” is as defined above.

“Alkylamino” refers to the group alkyl-NR′—, wherein R′ is selected fromhydrogen and alkyl.

“Arylamino” refers to the group aryl-NR′—, wherein R′ is selected fromhydrogen, aryl and heteroaryl.

“Alkoxyamino” refers to a radical —N(H)OR where R represents an alkyl orcycloalkyl group as defined herein.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkylarylamino” refers to a radical —NRR′ where R represents an alkylor cycloalkyl group and R′ is an aryl as defined herein.

“Alkylsulfonyl” refers to a radical —S(O)₂R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylsulfinyl” refers to a radical —S(O)R where R is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylthio” refers to a radical —SR where R is an alkyl or cycloalkylgroup as defined herein that may be optionally substituted as definedherein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino” refers to the radical —NH₂.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R)₂ whereeach R is independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl, and whereboth R groups are joined to form an alkylene group. When both R groupsare hydrogen, —N(R)₂ is an amino group.

“Aminocarbonyl” or “amido” refers to the group —C(O)NRR where each R isindependently hydrogen, alkyl, aryl and cycloalkyl, or where the Rgroups are joined to form an alkylene group.

“Aminocarbonylamino” refers to the group —NRC(O)NRR where each R isindependently hydrogen, alkyl, aryl or cycloalkyl, or where two R groupsare joined to form an alkylene group.

“Aminocarbonyloxy” refers to the group —OC(O)NRR where each R isindependently hydrogen, alkyl, aryl or cycloalky, or where the R groupsare joined to form an alkylene group.

“Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein.

“Arylamino” means a radical —NHR where R represents an aryl group asdefined herein.

“Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl is asdefined herein.

“Arylsulfonyl” refers to a radical —S(O)₂R where R is an aryl orheteroaryl group as defined herein.

“Azido” refers to the radical —N₃.

“Carbamoyl” refers to the radical —C(O)N(R)₂ where each R group isindependently hydrogen, alkyl, cycloalkyl or aryl, as defined herein,which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Carboxyamino” refers to the radical —N(H)C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like.

“Substituted cycloalkyl” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a cycloalkyl grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Cycloalkoxy” refers to the group —OR where R is cycloalkyl. Suchcycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxyand the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Substituted cycloalkenyl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to acycloalkenyl group having 1 or more substituents, for instance from 1 to5 substituents, and particularly from 1 to 3 substituents, selected fromthe group consisting of acyl, acylamino, acyloxy, alkoxy, substitutedalkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo. Preferredhalo groups are either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R¹⁴, —O⁻, ═O,—OR¹⁴, —SR¹⁴, —S⁻, ═S, —NR¹⁴R¹⁵, ═NR¹⁴, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R¹⁴, —OS(O₂)O⁻,—OS(O)₂R¹⁴, —P(O)(O⁻)₂, —P(O)(OR¹⁴)(O⁻), —OP(O)(OR¹⁴)(OR¹⁵), —C(O)R¹⁴,—C(S)R¹⁴, —C(O)OR¹⁴, —C(O)NR¹⁴R¹⁵, —C(O)O⁻, —C(S)OR¹⁴, —NR¹⁶C(O)NR¹⁴R¹⁵,—NR¹⁶C(S)NR¹⁴R¹⁵, —NR¹⁷C(NR¹⁶)NR¹⁴R¹⁵ and —C(NR¹⁶)NR¹⁴R¹⁵, where each Xis independently a halogen; each R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl,substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR¹⁸R¹⁹, —C(O)R¹⁸ or —S(O)₂R¹⁸ or optionally R¹⁸ andR¹⁹ together with the atom to which they are both attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R¹⁸ and R¹⁹are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedalkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

Examples of representative substituted aryls include the following

In these formulae one of R^(6′) and R^(7′) may be hydrogen and at leastone of R^(6′) and R^(7′) is each independently selected from alkyl,alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy,heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR¹⁰OCOR¹¹,NR¹⁰SOR¹¹, NR¹⁰SO₂R¹⁴ COOalkyl, COOaryl, CONR¹⁰R¹¹, CONR¹⁰OR¹¹, NR¹⁰R¹¹,SO₂NR¹⁰R¹¹, S-alkyl, S-alkyl, SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl;or R^(6′) and R^(7′) may be joined to form a cyclic ring (saturated orunsaturated) from 5 to 8 atoms, optionally containing one or moreheteroatoms selected from the group N, O or S. R¹⁰, R¹¹, and R¹² areindependently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl,cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl,substituted or hetero alkyl or the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, tetrahydroisoquinoline, isothiazole,isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, tetrahydroquinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. Particularly, heteroaryl can includeother saturated ring systems, and can therefore be derived fromindoline, indolizine, tetrahydroquinoline, and tetrahydroisoquinoline.Preferably, the heteroaryl group is between 5-20 membered heteroaryl,with 5-10 membered heteroaryl being particularly preferred. Particularheteroaryl groups are those derived from thiophene, pyrrole,benzothiophene, benzofuran, indole, pyridine, pyrimidine, quinoline,tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, imidazole,oxazole and pyrazine.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁴, O, and S, where R⁴ isas defined herein.

Examples of representative cycloheteroalkyls include the following

wherein each X is selected from CR⁴ ₂, NR⁴, O and S; and each Y isselected from NR⁴, O and S, and where R^(6′) is R², R² and R⁴ being asdefined herein.

Examples of representative cycloheteroalkenyls include the following:

wherein each X is selected from CR⁴, NR⁴, O and S; and each Y isselected from carbonyl, N, NR⁴, O and S, where R⁴ is as defined herein.

Examples of representative aryl having hetero atoms containingsubstitution include the following:

wherein each X is selected from C—R⁴, CR⁴ ₂, NR⁴, O and S; and each Y isselected from carbonyl, NR⁴, O and S, where R⁴ is as defined herein.

“Hetero substituent” refers to a halo, O, S or N atom-containingfunctionality that may be present as an R⁴ in a CR⁴ group present assubstituents directly on W or Z of the compounds of this invention ormay be present as a substituent in the “substituted” aryl, heteroaryland aliphatic groups present in the compounds.

Examples of hetero substituents include:

-   -   -halo,    -   —NO₂, —NH₂, —NHR, —N(R)₂,    -   —NRCOR, —NRSOR, —NRSO₂R, OH, CN, CO₂R,    -   —CO₂H,    -   —O—R,    -   —CON(R)₂, —CONROR,    -   —SO₃H, —S—R, —SO₂N(R)₂,    -   —S(O)R, and —S(O)₂R,        wherein each R is independently an aryl or aliphatic, optionally        with substitution. Among hetero substituents containing R        groups, preference is given to those materials having aryl and        alkyl R groups as defined herein. Where feasible, each R may        include hydrogen. Also, where feasible, two R groups when on        same atom may join to form a heterocyclic ring of 3-8 atoms. For        example, two R groups of NR², SO₂NR², and CONR² may join,        together with the N atom, to form a N-morpholino, N-pyrrolo,        N-piperidino, and N-pyrazolylo ring. Preferred hetero        substituents are those listed above.

As used herein, the term “cycloheteroalkyl” refers to a stableheterocyclic non-aromatic ring and fused rings containing one or moreheteroatoms independently selected from N, O and S. A fused heterocyclicring system may include carbocyclic rings and need only include oneheterocyclic ring. Examples of heterocyclic rings include, but are notlimited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl,and are shown in the following illustrative examples:

optionally substituted with one or more groups selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.Substituting groups include carbonyl or thiocarbonyl which provide, forexample, lactam and urea derivatives. In the examples, M is CR⁷, NR², O,or S; Q is O, NR² or S, where R² is as defined herein. R⁷ and R⁸ areindependently selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Dihydroxyphosphoryl” refers to the radical —PO(OH)₂.

“Substituted dihydroxyphosphoryl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to adihydroxyphosphoryl radical wherein one or both of the hydroxyl groupsare substituted. Suitable substituents are described in detail below.

“Aminohydroxyphosphoryl” refers to the radical —PO(OH)NH₂.

“Substituted aminohydroxyphosphoryl” includes those groups recited inthe definition of “substituted” herein, and particularly refers to anaminohydroxyphosphoryl wherein the amino group is substituted with oneor two substituents. Suitable substituents are described in detailbelow. In certain embodiments, the hydroxyl group can also besubstituted.

“Thioalkoxy” refers to the group —SR where R is alkyl.

“Substituted thioalkoxy” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a thioalkoxy grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to aradical such as RS— wherein R is any substituent described herein.

“Sulfonyl” refers to the divalent radical —S(O₂)—. “Substitutedsulfonyl” refers to a radical such as S(O₂)—R wherein R is anysubstituent described herein. “Aminosulfonyl” or “Sulfonamide” refers tothe radical H₂N(O₂)S—, and “substituted aminosulfonyl” “substitutedsulfonamide” refers to a radical such as R₂N(O₂)S— wherein each R isindependently any substituent described herein.

“Sulfoxide” refers to the divalent radical —S(O)—. “Substitutedsulfoxide” refers to a radical such as S(O)—R, wherein R is anysubstituent described herein.

“Sulfone” refers to the group —SO₂R. In particular embodiments, R isselected from H, lower alkyl, alkyl, aryl and heteroaryl.

“Thioaryloxy” refers to the group —SR where R is aryl.

“Thioketo” refers to the group ═S.

“Thiol” refers to the group —SH.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

“Pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to a non toxic, acceptablecationic counter-ion of an acidic functional group. Such cations areexemplified by sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium cations, and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention,which have cleavable groups and become by solvolysis orunder physiological conditions the compounds of the invention which arepharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

“Solvate” refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. Conventional solvents includewater, ethanol, acetic acid and the like. The compounds of the inventionmay be prepared e.g. in crystalline form and may be solvated orhydrated. Suitable solvates include pharmaceutically acceptablesolvates, such as hydrates, and further include both stoichiometricsolvates and non-stoichiometric solvates.

“Subject” includes humans. The terms “human,” “patient” and “subject”are used interchangeably herein.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” can vary depending on the compound, the disease and itsseverity, and the age, weight, etc., of the subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder, or even preventing the same.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups,a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of π electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base. Representative enol—ketostructures and equilibrium are illustrated below:

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art.

The Compounds

The present invention provides tetrahydronaphthyridine compounds usefulfor preventing and/or treating a broad range of conditions, among them,arthritis, Parkinson's disease, Alzheimer's disease, stroke, uveitis,asthma, myocardial infarction, the treatment and prophylaxis of painsyndromes (acute and chronic or neuropathic), traumatic brain injury,acute spinal cord injury, neurodegenerative disorders, alopecia (hairloss), inflammatory bowel disease and autoimmune disorders or conditionsin mammals.

In a first embodiment, the present invention providestetrahydronaphthyridine compounds according to formula (1):

wherein

-   -   A and B are independently selected from CH₂, CR²R⁴, CO, CS, NR¹,        and NR²;    -   Y is independently selected from CH₂, CR²R⁴, NR¹, and NR²;    -   W and Z are independently selected from CR⁴ and N, provided that        W and Z both can not be N;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   R² is selected from hydrogen, substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl,        substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof.

More particularly there is provided an amine compound capable ofmodifying ion channels, in vivo, having a formula:

wherein

-   -   A and B are independently selected from CH₂, CR^(2′)R^(2′), CO,        CS and NR^(2′);    -   Y is independently selected from CH₂, CR^(2′)R^(2′) and NR^(2′);    -   W and Z are independently selected from CR⁴ and N, provided that        W and Z both can not be N;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   each of R² and R^(2′) is selected from hydrogen, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆        cycloalkyl, substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof.

Compounds according to formula (1) may, for example be further definedas follows:

-   -   when A, B and Y all are CH₂s then R³ is not        alkoxy-4-quinazolinon-2-yl;    -   when A, B and Y all are CH₂s, W is N, Z is CR⁴, then R⁴ is not        alkylamino, dialkylamino or alkylarylamino; and    -   when A is CO, then R³is not hydrogen, alkyl or unsubstituted        phenyl.

Suitably A, B and Y independently represent CR^(2′)R^(2′).

Suitably R¹ is substituted aryl or heteroaryl; R² is H or lower alkyl,eg. H; and R³ is substituted or unsubstituted aryl, eg. R³ issubstituted aryl.

When R³ represents substituted aryl, suitably the substitution on arylis independently selected from halo, amido, alkyl, alkoxy, sulfonyl,sulfonamidyl, haloalkyl and trihaloalkyl. The substitution on aryl isalso suitably independently selected from Cl, F, CF₃, Me, OMe,SO₂R^(2′), NR^(2′)R^(2′), and SO₂NR^(2′)R^(2′). The substitution on arylis also suitably independently selected from 4-halo, 4-amido, 4-alkyland 4-alkoxy.

Substitution on aryl may, for example, be on the 2- or the 4-position.

Alternatively R¹ may represent substituted aryl or heteroaryl; R² is Hor lower alkyl, eg. H; and R³ is substituted or unsubstitutedheteroaryl.

For example, R³ may be substituted or unsubstituted pyridyl. For exampleR³ may be substituted 2-pyridyl. Substitution on 2-pyridyl may be, forexample, at the 3-position. Alternatively the substitution on 2-pyridylmay be at the 4-position. Alternatively the substitution on 2-pyridylmay be at the 5-position. Alternatively the substitution on 2-pyridylmay be at the 6-position.

For example, R³ may represent 3,5- or 3,4-disubstituted 2-pyridyl.

Suitably, substitutions on 2-pyridyl are independently selected fromhalo, amido, alkyl, alkoxy, cyano, sulfonyl, sulfonamidyl, haloalkyl andtrihaloalkyl. Substitutions are also independently selected from Cl, F,CN, CF₃, Me, OMe, SO₂R^(2′), NR^(2′)R^(2′), and SO₂NR^(2′)R^(2′).Substitutions are also independently selected from Cl, CN, CF₃, NR¹R²and SO₂NR¹R².

In certain embodiments of the invention W and Z both are CR⁴.Alternatively W is CR⁴ and Z is N. Alternatively, W is N and Z is CR⁴.Suitably R⁴ is selected from H, cyano, amido, and a group represented byX—(CR^(2′)R^(2′))_(n)—R^(3″); wherein X is a bond, O, S, SO, SO₂, orNR^(2′); each R^(2′) is selected from hydrogen, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆cycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted aralkyl; R^(3″) is selected from a hydrogen, a heterosubstituent and aryl, heteroaryl, heteroalkyl, cycloalkyl,cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl,and bicycloheteroaryl ring; and n is selected from 0-4; provided when Xis other than a bond, R^(3″) is hetero substituent then n is at least 2.In a particular embodiment, R⁴ may be X—(CR^(2′)R^(2′))_(n)—R^(3″),where X may be a bond, each R^(2′) may be H; and n is 0-4.Alternatively, X may be O, S, SO or SO₂; each R^(2′) may be H; and n is2-4.

In the above embodiment, R^(3″) may be substituted or unsubstitutedcycloalkyl, cycloheteroalkyl, aryl or heteroaryl, and in a particularembodiment, R^(3″) is a hetero substituent. In a specific embodiment,R^(3″) is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me,CONH₂, CONMe₂ and SO₂NMe₂. For example R⁴ may represent H.

In further embodiments of the invention, R¹ is substituted aryl and R²is H. Suitably, substitution on aryl is independently selected fromalkyl, trihaloalkyl, alkoxy, and dialkylamino, eg. is independentlyselected from t-Bu, iso-Pr, OMe, OCF₃, Br and NR¹R². For example, thesubstitution is at the 3-position or the 4-position. For example, R¹ is3,4-disubstituted aryl.

In other embodiments of the invention R¹ is substituted heteroaryl andR² is H. For example, R¹ is substituted pyridyl, eg. 2-pyridyl; eg.wherein the substitution on pyridyl is selected from the 3-position, the4-position and the 5-position. For example, R¹ is 3,4- or3,5-disubstituted 2-pyridyl.

Alternatively R¹ is substituted 3-pyridyl; eg. wherein the substitutionon pyridyl is at the 4- or 5- position.

Substitutions on pyridyl may, for example, be independently selectedfrom halo, amido, alkyl, alkoxy, cyano, sulfonyl, sulfonamidyl,haloalkyl and trihaloalkyl. Suitably, substitutions may be independentlyselected from t-Bu, Cl, F, iso-Pr, OMe, OCF₃, OCHF₂, SO₂CF₃, SO₂R^(2′),SO₂NR^(2′)R^(2′), CN, C(Me)₂CN and NR¹R². Suitably, substitutions mayindependently selected from alkyl, trihaloalkyl, alkoxy, anddialkylamino, eg. are independently selected from t-Bu, iso-Pr, OMe,OCF₃, Br and NR¹R².

A, B and Y may, for example, all represent CH₂. Alternatively A mayrepresent CO, and B and Y may represent CH₂. Alternatively B mayrepresent CO, and A and Y may represent CH₂.

Referring further to the compounds of formula (1), in certainembodiments, z is CH or CX₃ where X is halo.

Also referring to the compounds of formula (1), in certain embodiments,R³ can be substituted or unsubstituted phenyl, substituted orunsubstituted thiophene, substituted or unsubstituted pyrrole,substituted or unsubstituted di-pyridine, or halo-substituted methylpyridine.

Also referring the compounds of formula (1), in certain embodiments, oneof R¹ or R² is H and the other of R¹ and R² can be aryl, substituted orunsubstituted aryl (especially hetero-substituted aryl), substituted orunsubstituted pyridine, especially t-butyl pyridine.

In a further embodiment, the present invention provides aryl aminecompounds according to formula (2):

wherein

-   -   A, B and Y are independently selected from CH₂, CO, NR¹, NR²,        and CR¹R⁴;    -   W and Z are independently selected from CR¹R⁴, CO, NR¹, NR², O,        S and SO₂;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   R² is selected from hydrogen, substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl,        substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof.

Suitably, W and Z are independently selected from CH₂, CO, NR¹, NR₂, O,S and SO₂.

In a particular embodiment of the compound of formula (2), A, B and Yare independently selected from CO, NR^(2′), and CR^(2′)R^(2′); W and Zare independently selected from CH₂, CO, NR^(2′), O, S and SO₂; and eachof R^(2′) is selected from hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted aralkyl. Forexample, A, B and Y each represent CH₂.

In a still further embodiment, the present invention provides aminecompounds according to formula (3):

wherein

-   -   A, B and Y are independently selected from CH₂, CO, NR¹, NR²,        and CR¹R⁴;    -   W is selected from CR¹R⁴, CO, NR¹, NR², O, S and SO₂;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   R² is selected from hydrogen, substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl,        substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof.

Suitably, W is independently selected from CH₂, CO, NR¹, NR², O, S andSO₂.

In a particular embodiment of the compound of formula (3), A, B and Yare independently selected from CO, NR^(2′), and CR^(2′)R^(2′); W and Zare independently selected from CH₂, CO, NR^(2′), O, S and SO₂; and eachof R^(2′) is selected from hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted aralkyl.

Referring further to the compound of formula (3), in specificembodiments, W is O, R³ is a pyridine, one of R¹ or R² is H and theother of R¹ and R² is a hetero substituted aryl.

In a further particular embodiment relating to the compounds of formula(2), the invention includes an amine compound capable of modifying ionchannels, in vivo, having a formula:

wherein

-   -   A and B are independently selected from CH₂, CR²R⁴, CO, CS, NR¹        and NR²;    -   Y is independently selected from CH₂, CR²R⁴, NR¹ and NR²;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   R² is selected from hydrogen, substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl,        substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R³ is selected from substituted or unsubstituted C₁-C₆ alkyl,        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof.

In a particular embodiment of the above compounds, A and B areindependently selected from CR^(2′)R^(2′), CO, CS, and NR^(2′); Y isindependently selected from CR^(2′)R^(2′), and NR^(2′); and each of R²and R^(2′) is selected from hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted aralkyl.

Among the compounds described above by formula (1), there is a generalpreference for materials wherein R₃ is a 6 membered aryl or heteroarylring.

In a particular embodiment, the compounds according to Formula (1) canbe described by the following formula:

wherein

-   -   A and B are independently selected from CH₂, CR²R⁴, CO, CS, NR¹,        and NR²;    -   Y is independently selected from CH₂, CR²R⁴, NR¹, and NR²;    -   W is selected from CR⁴ and N;    -   Z is CR⁴;    -   R¹ is selected from substituted and unsubstituted aliphatic,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted acyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted aralkyl, substituted or        unsubstituted heteroalkyl;    -   R² is selected from hydrogen, substituted or unsubstituted C₁-C₆        alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl,        substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R⁴ is selected from H, alkyl, substituted alkyl, acyl,        substituted acyl, substituted or unsubstituted acylamino,        substituted or unsubstituted alkylamino, substituted or        unsubstituted alkythio, substituted or unsubstituted alkoxy,        alkoxycarbonyl, substituted alkoxycarbonyl, substituted or        unsubstituted alkylarylamino, arylalkyloxy, substituted        arylalkyloxy, amino, aryl, substituted aryl, arylalkyl,        substituted or unsubstituted sulfoxide, substituted or        unsubstituted sulfone, substituted or unsubstituted sulfanyl,        substituted or unsubstituted aminosulfonyl, substituted or        unsubstituted arylsulfonyl, sulfuric acid, sulfuric acid ester,        substituted or unsubstituted dihydroxyphosphoryl, substituted or        unsubstituted aminodihydroxyphosphoryl, azido, carboxy,        substituted or unsubstituted carbamoyl, carboxyl, cyano,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted cycloheteroalkyl, substituted or unsubstituted        dialkylamino, halo, heteroaryloxy, substituted or unsubstituted        heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy,        nitro, and thio; and m is selected from 0-4;    -   or a pharmaceutically acceptable salt, solvate or prodrug        thereof;    -   and stereoisomers and tautomers thereof. Suitably m may be        selected from 0 to 3.

In a particular embodiment of the compound of the above variant formula,A, B and Y are CR^(2′)R^(2′); W is selected from CR⁴ and N; Z is CR⁴; R²is hydrogen; R^(2′) is hydrogen, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted C₁-C₆ cycloalkyl, substituted orunsubstituted aryl and substituted or unsubstituted aralkyl. Suitably A,B and Y may all be CH₂s, and m is selected from 0-3.

Further variant compounds of this formula may comprise the following:

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and m and n are independently selected from 0-3. Inthis variant, m may, for example represent 0; n may, for example,represent 0; R₅ may, for example, be selected from 4-t-Bu, 4-Cl, 4-F,4-iso-Pr, 4-OMe, 4-OCF₃, 4-OCHF₂, 4-SO₂CF₃, 4-SO₂R^(2′),4-SO₂NR^(2′)R^(2′), 4-C(Me)₂CN, 3,4-diCl and 4-NR^(2′)R^(2′); m may, forexample, represent 0; and n may, for example, represent 0;

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and m and n are independently selected from 0-3.Suitably, R⁵ may be selected from 4-t-Bu, 4-Cl, 4-F, 4-iso-Pr, 4-OMe,4-OCF₃, 4-OCHF₂, 4-SO₂CF₃, 4-SO₂R^(2′), 4-SO₂NR^(2′)R^(2′), 4-C(Me)2CN,3,4-diCl and 4-NR^(2′)R^(2′); m may, for example, represent 0; and nmay, for example, represent 0;

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and m and n are independently selected from 0-3.Suitably, R⁵ may be selected from 4-t-Bu, 4-Cl, 4-F, 4-iso-Pr, 4-OMe,4-OCF₃, 4-OCHF₂, 4-SO₂CF₃, 4-SO₂R^(2′), 4-SO₂NR^(2′)R^(2′), 4-C(Me)2CN,3,4-diCl and 4-NR^(2′)R^(2′); m may, for example, represent 0; and nmay, for example, represent 0;

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and m and n are independently selected from 0-3.Suitably, R⁵ may be selected from 4-t-Bu, 4-Cl, 4-F, 4-iso-Pr, 4-OMe,4-OCF₃, 4-OCHF₂, 4-SO₂CF₃, 4-SO₂R^(2′), 4-SO₂NR^(2′)R^(2′), 4-C(Me)2CN,3,4-diCl and 4-NR^(2′)R^(2′); m may, for example, represent 0; and nmay, for example, represent 0;

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OC F₂, and Cl; and m and n are independently selected from 0-3.Suitably, R⁵ may be selected from 4-t-Bu, 4-Cl, 4-F, 4-iso-Pr, 4-OMe,4-OCF₃, 4-OCHF₂, 4-SO₂CF₃, 4-SO₂R^(2′), 4-SO₂NR^(2′)R^(2′), 4-C(Me)2CN,3,4-deCl and 4-NR^(2′)R^(2′); m may, for example, represent 0; and nmay, for example, represent 0;

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and m and n are independently selected from 0-3.Suitably, R⁵ may be selected from 4-t-Bu, 4-Cl, 4-F, 4-iso-Pr, 4-OMe,4-OCF₃, 4-OCHF₂, 4-SO₂CF₃, 4-SO₂R^(2′), 4-SO₂NR^(2′)R^(2′), 4-C(Me)2CN,3,4-diCl and 4-NR^(2′)R^(2′); m may, for example, represent 0; and nmay, for example, represent 0;

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and m and n are independently selected from 0-3;and

wherein R⁵ is selected from R⁴, t-Bu, iso-Pr, CF₃, dialkylamino, Br,OCF₃, OCHF₂, and Cl; and n is from 0-3.

In the aforementioned structures, W and Z may, for example, bothrepresent CR⁴. Alternatively W may represent N and Z may represent CR⁴.Suitably R⁴ is selected from H, cyano, amido, and a group represented byX—(CR^(2′)R^(2′))_(n)—R^(3″); wherein X is a bond, O, S, SO, SO₂, orNR^(2′); each R^(2′) is selected from hydrogen, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆cycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted aralkyl; R^(3″) is selected from a hydrogen, a heterosubstituent and aryl, heteroaryl, heteroalkyl, cycloalkyl,cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl,and bicycloheteroaryl ring; and n is selected from 0-4; provided when Xis other than a bond, R^(3″) is hetero substituent then n is at least 2.In a particular embodiment, R⁴ may be X—(CR^(2′)R^(2′))_(n)—R^(3″),where X may be a bond, each R^(2′) may be H; and n is 0-4.Alternatively, X may be O, S, SO or SO₂; each R^(2′) may be H; and n is2-4.

In the above embodiment, R^(3″) may be substituted or unsubstitutedcycloalkyl, cycloheteroalkyl, aryl or heteroaryl, and in a particularembodiment, R^(3″) is a hetero substituent. In a specific embodiment,R^(3″) is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me,CONH₂, CONMe₂ and SO₂NMe₂. For example R⁴ may represent H. Suitably A, Band Y all are CH₂. Alternatively A and B are independently selected fromCH₂ and CHCH₃, and Y is CH₂. Alternatively A and B are independentlyselected from CH₂ and CO and Y is CH₂. Alternatively A and B areindependently selected from CO and CS and Y is NR².

Further variant compounds are defined by the formula:

wherein R¹ is heteroaryl and R^(5′) is selected from Cl, CF₃, F, OMe,SO₂Me and SO₂CF₃.

Suitably, R¹ is selected from substituted and unsubstituted pyridyl.Suitably the substitution is selected from t-Bu, Cl, F, iso-Pr, OMe,OCF₃, OCHF₂, SO₂CF₃, SO₂R^(2′), SO₂NR^(2′)R^(2′), CN, C(Me)₂CN, andNR^(2′)R^(2′).

Alternatively, R¹ may be selected from substituted or unsubstitutedindolyl, benzimidazolyl, indazolyl, tetrahydroquinoline andtetrahydroisoquinoline. In a particular aspect of the invention, thecompound is depicted by the following formula:

wherein

-   -   R^(1″) is selected from H, alkyl, and a group represented by        —(CR^(2′)R^(2′))_(n)—R^(3″);    -   each R^(2′) is selected from hydrogen, substituted or        unsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆        cycloalkyl, substituted or unsubstituted aryl and substituted or        unsubstituted aralkyl;    -   R^(3″) is selected from a hydrogen, a hetero substituent and        aryl, heteroaryl, heteroalkyl, cycloalkyl, cycloheteroalkyl,        cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,        bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl,        bicycloaryl, and bicycloheteroaryl ring; and    -   n is selected from 2-5.

In a particular embodiment, R⁴ is —(CR^(2′)R^(2′))_(n)—R^(3″) and eachR^(2′) may be H, in which instance, n may be 2-4. R^(3″) may also besubstituted or unsubstituted cycloalkyl, cycloheteroalkyl, aryl orheteroaryl. Particularly, R^(3″) may be substituted or unsubstituted

where R² is as defined herein. In a further particular embodiment,R^(3″) is a hetero substitutent, and more particularly, R^(3″) isselected from COOH, SMe, SO₂Me, OH, OEt, OMe, NEt₂, halo, NHSO₂Me,CONH₂, CONMe₂, SO₂NH₂, and SO₂NMe₂.

In one embodiment, W and Z are both CR⁴. Alternatively W is N and Z isCR⁴.

Suitably R⁴ is selected from H, cyano, amido, and a group represented byX—(CR^(2′)R^(2′))_(n)—R^(3″); wherein X is a bond, O, S, SO, SO₂, orNR^(2′); each R^(2′) is selected from hydrogen, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted C₁-C₆cycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted aralkyl; R^(3″) is selected from a hydrogen, a heterosubstituent and aryl, heteroaryl, heteroalkyl, cycloalkyl,cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl,and bicycloheteroaryl ring; and n is selected from 0-4; provided when Xis other than a bond, R^(3″) is hetero substituent then n is at least 2.In a particular embodiment, R⁴ may be X—(CR^(2′)R^(2′))_(n)—R^(3″),where X may be a bond, each R^(2′) may be H; and n is 0-4.Alternatively, X may be O, S, SO or SO₂; each R^(2′) may be H; and n is2-4.

In the above embodiment, R^(3″) may be substituted or unsubstitutedcycloalkyl, cycloheteroalkyl, aryl or heteroaryl, and in a particularembodiment, R^(3″) is a hetero substituent. In a specific embodiment,R^(3″) is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me,CONH₂, CONMe₂ and SO₂NMe₂. For example R⁴ may represent H.

Suitably A, B and Y are all CH₂. Alternatively A and B are independentlyselected from CH₂ and CHCH₃, and Y is CH₂.

Particular non-limiting examples of compounds corresponding to thestructural variant just described, are as follows:

In the instance of all of the above compounds, R⁵ may be selected from4-t-Bu, 4-Cl, 4-F, 4-iso-Pr, 4-OMe, 4-OCF₃, 4-OCHF₂, 4-SO₂CF₃,4-SO₂R^(2′), 4-SO₂NR^(2′)R^(2′), 4-C(Me)2CN, 3,4-diCl and4-NR^(2′)R^(2′). In the instance of all of the above compounds W and Zmay, for example, both represent CR⁴. Alternatively W may represent Nand Z may represent CR⁴. Suitably R⁴ is selected from H, cyano, amido,and a group represented by X—(CR^(2′)R^(2′))_(n)—R^(3″); wherein X is abond, O, S, SO, SO₂, or NR^(2′); each R^(2′) is selected from hydrogen,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedC₁-C₆ cycloalkyl, substituted or unsubstituted aryl and substituted orunsubstituted aralkyl; R^(3″) is selected from a hydrogen, a heterosubstituent and aryl, heteroaryl, heteroalkyl, cycloalkyl,cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, bicycloalkyl,bicycloheteroalkyl, bicycloalkenyl, bicycloheteroalkenyl, bicycloaryl,and bicycloheteroaryl ring; and n is selected from 0-4; provided when Xis other than a bond, R^(3″) is hetero substituent then n is at least 2.In a particular embodiment, R⁴ may be X—(CR^(2′)R^(2′))_(n)—R^(3″),where X may be a bond, each R^(2′) may be H; and n is 0-4.Alternatively, X may be O, S, SO or SO₂; each R^(2′) may be H; and n is2-4.

In the above embodiment, R^(3″) may be substituted or unsubstitutedcycloalkyl, cycloheteroalkyl, aryl or heteroaryl, and in a particularembodiment, R^(3″) is a hetero substituent. In a specific embodiment,R^(3″) is selected from COOH, SO₂Me, SMe, OH, OEt, OMe, NEt₂, NHSO₂Me,CONH₂ and CONMe₂. For example R⁴ may represent H. Suitably A, B and Yare all CH₂. Alternatively A and B are independently selected from CH₂and CHCH₃, and Y is CH₂. Alternatively A and B are independentlyselected from CH₂ and CO and Y is CH₂. Alternatively A and B areindependently selected from CO and CS and Y is NR².

Additional variant compounds within the scope of the present inventionare set forth in non-limiting fashion later on herein and in theexamples. It should be understood that these examples are forillustrative purposes only and are not to be construed as limiting thisinvention in any manner.

Further compounds related to Formula 3 of the invention are set forthbelow.

In certain aspects, the present invention provides prodrugs andderivatives of the compounds according to the formulae above. Prodrugsare derivatives of the compounds of the invention, which havemetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention, which arepharmaceutically active, in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

Pharmaceutical Compositions

When employed as pharmaceuticals, the amine compounds of this inventionare typically administered in the form of a pharmaceutical composition.Such compositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

Generally, the compounds of this invention are administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound-administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of this invention can be administered bya variety of routes including oral, rectal, transdermal, subcutaneous,intravenous, intramuscular, and intranasal. Depending on the intendedroute of delivery, the compounds of this invention are preferablyformulated as either injectable or oral compositions or as salves, aslotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the furansulfonic acidcompound is usually a minor component (from about 0.1 to about 50% byweight or preferably from about 1 to about 40% by weight) with theremainder being various vehicles or carriers and processing aids helpfulfor forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds, of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope of this invention.

The compounds of this invention can also be administered by atransdermal device. Accordingly, transdermal administration can beaccomplished using a patch either of the reservoir or porous membranetype, or of a solid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representativepharmaceutical compositions of this invention. The present invention,however, is not limited to the following pharmaceutical compositions.

Formulation 1—Tablets

A compound of formula I is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 240-270 mgtablets (80-90 mg of active amide compound per tablet) in a tabletpress.

Formulation 2—Capsules

A compound of formula I is admixed as a dry powder with a starch diluentin an approximate 1:1 weight ratio. The mixture is filled into 250 mgcapsules (125 mg of active amide compound per capsule).

Formulation 3—Liquid

A compound of formula I (125 mg), sucrose (1.75 g) and xanthan gum (4mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixedwith a previously made solution of microcrystalline cellulose and sodiumcarboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10mg), flavor, and color are diluted with water and added with stirring.Sufficient water is then added to produce a total volume of 5 mL.

Formulation 4—Tablets

The compound of formula I is admixed as a dry powder with a dry gelatinbinder in an approximate 1:2 weight ratio. A minor amount of magnesiumstearate is added as a lubricant. The mixture is formed into 450-900 mgtablets (150-300 mg of active amide compound) in a tablet press.

Formulation 5—Injection

The compound of formula I is dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/ml.

Formulation 6—Topical

Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted atabout 75° C. and then a mixture of a compound of formula I (50 g)methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate(10 g), and propylene glycol (120 g) dissolved in water (about 370 g) isadded and the resulting mixture is stirred until it congeals.

Methods of Treatment

The present amine compounds are used as therapeutic agents for thetreatment of conditions in mammals. Accordingly, the compounds andpharmaceutical compositions of this invention find use as therapeuticsfor preventing and/or treating neurodegenerative, autoimmune andinflammatory conditions in mammals including humans.

In a method of treatment aspect, this invention provides a method oftreating a mammal susceptible to or afflicted with a conditionassociated with arthritis, uveitis, asthma, myocardial infarction,traumatic brain injury, acute spinal cord injury, alopecia (hair loss),inflammatory bowel disease and autoimmune disorders, which methodcomprises administering an effective amount of one or more of thepharmaceutical compositions just described.

In yet another method of treatment aspect, this invention provides amethod of treating a mammal susceptible to or afflicted with a conditionthat gives rise to pain responses or that relates to imbalances in themaintenance of basal activity of sensory nerves. The present amines haveuse as analgesics for the treatment of pain of various geneses oretiology, for example acute, inflammatory pain (such as pain associatedwith osteoarthritis and rheumatoid arthritis); various neuropathic painsyndromes (such as post-herpetic neuralgia, trigeminal neuralgia, reflexsympathetic dystrophy, diabetic neuropathy, Guillian Barre syndrome,fibromyalgia, phantom limb pain, post-masectomy pain, peripheralneuropathy, HIV neuropathy, and chemotherapy-induced and otheriatrogenic neuropathies); visceral pain, (such as that associated withgastroesophageal reflex disease, irritable bowel syndrome, inflammatorybowel disease, pancreatitis, and various gynecological and urologicaldisorders), dental pain and headache (such as migraine, cluster headacheand tension headache).

In additional method of treatment aspects, this invention providesmethods of treating a mammal susceptible to or afflicted withneurodegenerative diseases and disorders such as, for exampleParkinson's disease, Alzheimer's disease and multiple sclerosis;diseases and disorders which are mediated by or result inneuroinflammation such as, for example traumatic brain injury, stroke,and encephalitis; centrally-mediated neuropsychiatric diseases anddisorders such as, for example depression mania, bipolar disease,anxiety, schizophrenia, eating disorders, sleep disorders and cognitiondisorders; epilepsy and seizure disorders; prostate, bladder and boweldysfunction such as, for example urinary incontinence, urinaryhesitancy, rectal hypersensitivity, fecal incontinence, benign prostatichypertrophy and inflammatory bowel disease; respiratory and airwaydisease and disorders such as, for example, allergic rhinitis, asthmaand reactive airway disease and chronic obstructive pulmonary disease;diseases and disorders which are mediated by or result in inflammationsuch as, for example rheumatoid arthritis and osteoarthritis, myocardialinfarction, various autoimmune diseases and disorders, uveitis andatherosclerosis; itch/pruritus such as, for example psoriasis; alopecia(hair loss); obesity; lipid disorders; cancer; blood pressure; spinalcord injury; and renal disorders method comprises administering aneffective condition-treating or condition-preventing amount of one ormore of the pharmaceutical compositions just described.

As a further aspect of the invention there is provided the present aminecompounds for use as a pharmaceutical especially in the treatment orprevention of the aforementioned conditions and diseases. We alsoprovide use of a present amine compound in the manufacture of amedicament for the treatment or prevention of one of the aforementionedconditions and diseases.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions, such asneurodegenerative and autoimmune conditions, the regimen for treatmentusually stretches over many months or years so oral dosing is preferredfor patient convenience and tolerance. With oral dosing, one to five andespecially two to four and typically three oral doses per day arerepresentative regimens. Using these dosing patterns, each dose providesfrom about 0.01 to about 20 mg/kg of the amide derivative, withpreferred doses each providing from about 0.1 to about 10 mg/kg andespecially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses.

When used to prevent the onset of a neurodegenerative, autoimmune orinflammatory condition, the amide derivatives of this invention will beadministered to a patient at risk for developing the condition,typically on the advice and under the supervision of a physician, at thedosage levels described above. Patients at risk for developing aparticular condition generally include those that have a family historyof the condition, or those who have been identified by genetic testingor screening to be particularly susceptible to developing the condition.

The compounds of this invention can be administered as the sole activeagent or they can be administered in combination with other agents,including other active amide derivatives.

General Synthetic Procedures

The tetrahydronaphthyridine compounds of this invention can be preparedfrom readily available starting materials using the following generalmethods and procedures. It will be appreciated that where typical orpreferred process conditions (i.e., reaction temperatures, times, moleratios of reactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

Amide derivatives of this invention, for example, may be prepared by thereaction of a chloro derivative with an appropriately substituted amineand the product isolated and purified by known standard procedures. Suchprocedures include (but are not limited to) recrystallization, columnchromatography or HPLC. The following schemes are presented with detailsas to the preparation of representative tetrahydronaphthyridines thathave been listed hereinabove. The compounds of the invention may beprepared from known or commercially available starting materials andreagents by one skilled in the art of organic synthesis.

Synthetic Scheme 1

VariousN-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminederivatives are prepared using a general procedure described below.Accordingly, ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochlorideis reacted with formamidine acetate to yield7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one, which, inturn, is reacted with POCl₃ to afford the 4-chloro derivative. Theintermediate chloro derivative is then condensed with substitutedaniline or amine to give the desiredN-substituted-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine.Debenzylation using standard procedures known in the art followed bynucleophilic displacement of an appropriate 2-halo-pyridine yields theappropriateN-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine.As a representative example, synthesis ofN-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineis depicted in Scheme 1.

Conversly,N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminederivatives are prepared by first deprotecting the7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one andreacting the product with an appropriate 2-halo-pyridine to give the7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-onewhich is reacted with POCl3 followed by condensation with an appropriateaniline or amine to yield the appropriate the appropriateN-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine.As a representative example, synthesis ofN-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineis depicted in Scheme 2.

The 2-substituted pyrido[3,4-d]pyrimidin-4-one derivatives are preparedusing the synthetic sequence given below. The intermediate7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4(3H)-oneis formed by reaction of ethyl 1-benzyl-3-oxopiperidine-4-carboxylatehydrochloride with thiourea. This intermediate methylthio derivative isthen subjected to synthetic sequence outlined above (Scheme 2) to givethe appropriateN-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-aminederivative, which is oxidized to the corresponding sulfone derivativeand in turn reacted with an appropriate nucleophile to give theanalogous2-substituted-N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminederivative. As a representative example, synthesis ofN-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-methoxypyrido[3,4-d]pyrimidin-4-amineis depicted in Scheme 3.

Conversely, 2-chloroacetamidine hydrochloride is reacted with anappropriate nucleophile to form an appropriate amidine derivative. Theamidine is reacted with ethyl 1-benzyl-3-oxopiperidine-4-carboxylatehydrochloride to afford the intermediate2-substituted-N-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminederivative. This intermediate pyrido[3,4-d]pyrimidin-4-amine is thensubjected to the reaction sequence described in Scheme 2 to yieldappropriately 2-substitutedN-substituted-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminederivative. As a representative example, synthesis ofN-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amineis depicted in Scheme 4.

Appropriate N-arylsubstituted-5,6,7,8-tetrahydro-7-arylpyrido[3,4-d]pyrimidin-4-amine,obtained by following synthetic scheme 2, are prepared by the reactionof the correspondingN-substituted-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine with anappropriate aryl boronic acid in the presence of copper acetate andtriethylamine. As a representative example, preparation ofN-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-m-tolylpyrido[3,4-d]pyrimidin-4-amineis depicted in Scheme 5.

Appropriate7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine derivatives are prepared starting from1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline. The nitroquinolinederivate is reacted with appropriate alkylating agent to give theN-substituted nitroquinoline, which is reduced using standard proceduresknown in the art to yield 7-aminoquinoline derivative. The resultingaminoquinoline derivated is then condensed with the appropriate4-chloro-7-(pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine togive the desired7-(pyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethyl-1-substituted)quinolin-7-yl)pyrido[3,4-d]pyrimidin-4-aminederivative. As a representative example, preparation of theN-morpholionethyl derivative is depicted in Scheme 6.

A similar sequence of reactions using substituted amidines, and setforth in the scheme presented below, gives rise to 2-substitutedproducts. For example, trifluoromethyl amidine can be employed in thesimilar sequence of reactions to afford 2-trifluoromethyl substitutedproducts.

Similarly, another sequence of reactions, as depicted in Scheme 8, usingsubstituted amidines can be employed to prepare 2-substitutedderivatives.

The following synthetic and biological examples are offered toillustrate this invention and are not to be construed in any way aslimiting the scope of this invention. In the examples below, alltemperatures are in degrees Celsius (unless otherwise indicated). Thesyntheses of these representative compounds were carried out inaccordance with the methods set forth above and using the appropriatereagents, starting materials and purification methods known to thoseskilled in the art.

EXEMPLARY COMPOUNDS OF THE INVENTION

The following compounds have been prepared according to the methods ofthe invention. Corresponding compounds have been recited hereinabove andin the claims. Unless otherwise indicated, reactions in microwave werecarried out in Emrys Optimizer or Smith Creator microwave modelsmanufactured by Personal Chemistry, Inc.

EXAMPLES Example 17-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A. 7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one

1-Benzyl-3-ethoxycarbonyl-4-piperidone hydrochloride (12.89 g, 43.3mmol) was suspended in a sodium methoxide solution in methanol (25%wt/wt, 50 mL, 216.2 mmol) and formamidine acetate (5.4 g, 51.9 mmol) wasadded to the mixture. The reaction mixture was refluxed until all of thestarting material was consumed (2 h). The methanol was removed undervacuum, and the resulting white solid was dissolved in a 3:1 mixture ofchloroform: isopropanol. The mixture was washed with water and brine,dried over Na₂SO₄, filtered and evaporated to give the desired productas a white solid (9.4 g, 90%).

MS: M+H=242. ¹H NMR (DMSO-d6): δ 2.29 (t, 5.8 Hz, 2H); 2.61 (t, 5.8 Hz,2H); 3.26 (s, 2H); 3.64 (s, 2H); 7.21-7.36 (m, 6H); 7.96 (s, 1H).

B. 7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

7-Benzyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one (9.4 g, 39mmol) was dissolved in anhydrous 1,2-dichloroethane and stirred underN₂(g) atmosphere. To the mixture was added POCl₃ (29 mL, 312 mmol),followed by N,N-dimethylaniline (4.75 g, 39 mmol). The mixture wasrefluxed for 2 h and the solvents were removed under vacuum to give ared residue. The residue was dissolved in 20 mL of ethyl acetate and 20ml of water was added. The solution was neutralized with ice and solidNaHCO₃. After neutralization, ethyl acetate was added and the organiclayer was washed with water and brine. The organic layer was dried overNa₂SO₄ and the solvents were removed under vacuum. The resulting redresidue was purified using a gradient of ethyl acetate:hexane (0-100%)to give the desired compound as yellow crystals (3.8 g, 38%).

MS: M+H=260. ¹H NMR (DMSO-d6): δ 2.80 (t, 5.6 Hz, 2H), 2.92 (t, 5.6 Hz,2H), 3.57 (s, 2H), 3.76 (s, 2H), 7.24-7.40 (m, 5H), 8.80 (s, 1H).

C.7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (0.6 g, 2.3mmol) was dissolved in anhydrous dioxane (2 mL) and4-(trifluoromethyl)aniline was added (0.43 mL, 3.45 mmol), followed byHI/H₂O (0.2 ml, 47%). The mixture was heated at 130° C. in a sealed tubefor 10 min in a microwave (Smith creator model, Personal Chemistry). Thesolvents were removed under vacuum and the residue was dissolved inethyl acetate and washed with sat. NaHCO₃ and brine. The organic layerwas dried over Na₂SO₄, filtered and evaporated to give the desiredcompound as a yellow solid (800 mg, 91%) which was used as such for thenext step.

M+H=385.

D.N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(1.5 g, 3.9 mmol) was dissolved in methanol (25 mL) and palladiumhydroxide was added (1.5 g, 20% wt). The mixture was shaken on a ParrShaker under H₂(g) atmosphere (60 PSI) for 3 days. The mixture wasfiltered through celite and evaporated to give 1.0 g of material as ayellow solid (87%), which was used as such for the next step.

MS: M+H=295. ¹H NMR (DMSO-d6): δ 2.68 (t, 5.6 Hz, 2H), 3.05 (t, 5.6 Hz,2H), 3.84 (s, 2H), 7.66 (d, 8.6 Hz, 2H), 7.94 (d, 8.6 Hz, 2H), 8.46 (s,1H), 8.61 (s, 0.8H).

E.7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(700 mg, 3.4 mmol) was dissolved in a mixture ofdioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added2,3-dichloropyridine (1.5 g, 10.2 mmol) and N,N-diisopropylethylamine(0.87 mL, 5.1 mmol). The mixture was heated in a sealed tube at 150° C.in microwave (Model, Personal Chemistry) for 16 h. The solvents wereremoved under vacuum and the residue was dissolved in ethyl acetate andwashed with sat. NaHCO₃ and brine. The organic layer was dried overNa₂SO₄, filtered and evaporated to give a brown residue. The residue waspurified using a gradient of ethyl acetate:hexane (0-100%) to give thedesired compound as an off-white powder (340 mg, 26%).

MS: M+H=406. ¹H NMR (DMSO-d6): δ 2.92 (t, 5.6 Hz, 2H), 3.63 (t, 5.6 Hz,2H), 4.44 (s, 2H), 7.08 (dd, 7.6 Hz, 4.7 Hz, 1H), 7.67 (d, 8.4 Hz, 2H),7.89 (dd, 7.7 Hz, 1.6 Hz, 1H), 7.94 (d, 8.4 Hz, 2H), 8.28 (dd, 4.7 Hz,1.6 Hz, 1H), 8.50 (s, 1H), 8.91 (brs, 1H).

Example 2N-(4-tert-Butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A mixture of 4-tert-butylbenzenamine (0.312 mL, 1.98 mmol) and7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.467 g,1.80 mmol), prepared as described in Example 1.B. in acetonitile (2 mL)was heated in a sealed tube at 170° C. in a microwave (Emrys Optimizermodel, Personal Chemistry) for five min. Upon cooling to roomtemperature, a precipitate formed. The mixture was diluted with hexane(5 mL) and the precipitate was collected by filtration to give 0.576 gof the title compound as a tan solid.

MS: M+H=373.

Example 3N-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminehydrochloride

A.N-(4-tert-Butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A mixture ofN-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.359 g, 0.96 mmol), prepared as described in Example 2, ammoniumformate (0.304 g, 4.82 mmol) and palladium (10% wt. on activated carbon,40 mg) in MeOH (5 mL) was stirred at r.t. for one h and then at 60° C.for two h. The mixture was cooled to r.t. and filtered over celite. Thefiltrate was concentrated under reduced pressure to give a white solidwhich was dissolved in water. The mixture was extracted twice with a 3:1mixture of chloroform:isopropanol. The combined organic extracts weredried over sodium sulfate and concentrated to dryness to give 0.26 g(96%) of the title compound which was used directly without furtherpurification.

MS: M+H=283.

B.N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminehydrochloride

A mixture ofN-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine0.173 g, 0.61 mmol), 2,3-dichloropyridine (0.91 g, 0.61 mmol) andpotassium carbonate (0.234 g, 1.84 mmol) in DMF was heated in a sealedtube in a microwave (Emrys Optimizer model, Personal Chemistry) at 200°C. for 2 h. The mixture was cooled to r.t. and diluted with water (30mL). The mixture was extracted with ethyl acetate (3×30 mL). Thecombined organic extracts were washed with brine, dried over sodiumsulfate and concentrated to leave an oil. The product was purified bysilica gel chromatography (ethyl acetate/hexane gradient) to obtain0.035 g of the title compound as a light yellow oil. The oil wasdissolved in 1 ml ethyl acetate and treated with 1.0 M HCl in diethylether (0.09 mL). The resulting solid was collected by filtration, washedwith diethyl ether and dried to give 0.030 g light yellow solid.

MS: M+H=394. ¹H NMR (DMSO-d6): δ 1.30 (s, 9H), 2.83 (t, 5.6 Hz, 2H),3.74 (t, 5.6 Hz, 2H), 4.55 (s, 2H), 7.10 (dd, 7.9 Hz, 4.7 Hz, 1H),7.42-7.50 (m, 4H), 7.92 (dd, 7.6 Hz, 1.6 Hz, 1H), 8.26 (dd, 4.7 Hz, 1.6Hz, 1H), 8.75 (s, 1H), 10.04 (brs, 1H).

Example 4N-(4-tert-Butylphenyl)-7-(3-(trifluoromethyl)pyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-aminehydrochloride

The title compound was prepared using the general procedure set forth inExample 3, above, by heating a mixture of2-chloro-3-(trifluoromethyl)pyridine (0.108 g, 0.59 mmol),N-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(Example 3.A) (0.112 g, 0.40 mmol) and potassium carbonate (0.16 g, 1.19mmol) in DMF (2 mL) for 1 h.

MS: M+H=428. ¹H NMR (DMSO-d6): δ 1.30 (s, 9H), 2.81 (t, 5.2 Hz, 2H),3.62 (t, 5.6 Hz, 2H), 4.46 (s, 2H), 7.28 (dd, 7.6 Hz, 4.9 Hz, 1H), 7.43(d, 8.8 Hz, 2H), 7.49 (d, 8.8 Hz, 2H), 8.17 (dd, 7.6 Hz, 1.7 Hz, 1H),8.57 (dd, 4.9 Hz, 1.7 Hz, 1H), 8.69 (s, 1H), 9.72 (brs, 0.7H).

Example 5N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-aminehydrochloride

A.7-Benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4(3H)-one

A mixture of 1-benzyl-3-ethoxycarbonyl-4-piperidone hydrochloride (0.285g, 0.96 mmol), 2-chloroacetamidine hydrochloride (0.149 g, 1.16 mmol)and sodium methoxide (1.9 ml of a 25% wt/wt solution in methanol) andmethanol (0.5 mL) was heated in a sealed tube in microwave (EmrysOptimizer model, Personal Chemistry) at 100° C. for 15 min. The mixturewas allowed to cool to r.t. and concentrated under reduced pressure toleave a brown solid. The solid was taken up in water (30 mL) andextracted with a 3:1 mixture of chloroform:isopropanol (3×30 mL). Thecombined organic extracts were dried over sodium sulfate andconcentrated to dryness to leave the title compound (0.196 g, 72%) whichwas used directly without further purification.

MS: M+H=286.

B.7-Benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidine

A mixture of7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4(3H)-one(2.01 g, 7.04 mmol), phosphorus oxychloride (5.16 mL, 56.35 mmol) andN,N-dimethylaniline (0.89 mL, 7.04 mmol) in 1,2-dichloroethane washeated to 80° C. for two h. The mixture was allowed to cool to r.t. andpoured over crushed ice (100 mL). The mixture was made basic (pH=˜8) bythe addition of saturated aqueous sodium bicarbonate and extracted withethyl acetate (200 mL). The organic layer was dried over magnesiumsulfate and concentrated to leave a dark oil which was purified bysilica gel chromatography (ethyl acetate/hexane gradient) to yield 1.76g (82%) of the title compound as a brown oil.

MS: M+H=304.

C.N-(4-tert-Butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared using the general procedure set forth inExample 2, above, using7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidine(0.583 g, 1.92 mmol), 4-tert-butylbenzenamine (0.33 mL, 2.11 mmol) andacetonitrile (3 mL) to give 0.524 g (66%) of the title compound as anoff-white powder.

MS: M+H=417.

D.N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-aminehydrochloride

The title compound was prepared using the general procedure set forth inExample 3.A. usingN-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine(0.453 g, 1.09 mmol), ammonium formate (0.69 g, 10.87 mmol), palladium,10% wt. on activated carbon (100 mg) and MeOH (15 mL). 0.334 g (94%) Ofthe title compound was obtained as a white foam.

MS: M+H=327.

D.(4-tert-Butyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-methoxymethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-aminehydrochloride

The title compound was prepared using the general procedure set forth inExample 3.B. usingN-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine(0.105 g, 0.32 mmol), 2,3-dichloropyridine (0.071 g, 0.48 mmol),potassium carbonate (0.13 g, 0.96 mmol) and DMF (2 mL) and heating thereaction mixture for 1 h. The title compound was obtained as a lightyellow solid (15 mg, 10%)

MS: M+H=438. ¹H NMR (DMSO-d6): δ 1.30 (s, 9H), 2.80 (t, 4.8 Hz, 2H),3.41 (s, 3H), 3.62 (t, 4.8 Hz, 2H), 4.50 (s, 2H), 4.51 (s, 2H), 7.28(dd, 7.6 Hz, 4.9 Hz, 1H), 7.42 (d, 8.8 Hz, 2H), 7.56 (d, 8.8 Hz, 2H),8.17 (dd, 7.6 Hz, 1.7 Hz, 1H), 8.57 (dd, 4.9 Hz, 1.7 Hz, 1H), 9.8 (brs,0.6 H).

Example 6(4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-aminehydrochloride

The title compound was prepared using the general procedure set forth inExample 5 using 2-chloro-3-(trifluoromethyl)pyridine (0.084 g, 0.46mmol),N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine(0.101 g, 0.31 mmol), from Example 5.D., potassium carbonate (0.128 g,0.93 mmol) in DMF (2 mL). The title compound was obtained as a lightyellow solid.

MS: M+H=472. ¹H NMR (DMSO-d6): δ 1.30 (s, 9H), 2.81 (t, 5.6 Hz, 2H),3.42 (s, 3H), 3.74 (t, 5.6 Hz, 2H), 4.53 (s, 2H), 4.56 (s, 2H), 7.09(dd, 7.8 Hz, 4.7 Hz, 1H), 7.43 (d, 8.8 Hz, 2H), 7.54 (d, 8.8 Hz, 2H),7.91 (dd, 7.8 Hz, 1.6 Hz, 1H), 8.25 (dd, 4.7 Hz, 1.6 Hz, 1H), 9.83 (brs,0.5 H).

Example 7(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-[7-(3,3,3-trifluoro-propyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-aminehydrochloride

A.7-Benzyl-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared using the general procedure set forth inExample 2, above, using 2,3-dihydrobenzo[b][1,4]dioxin-6-amine (0.32 mL,2.63 mmol) and7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine, prepared asdescribed in Example 1.B. (0.621 g, 2.39 mmol) in acetonitile (3 mL).The title compound was obtained as a brown solid (0.756 g, 84%).

MS: M+H=375.

B.1-(4-(2,3-Dhydrobenzo[b][1,4]dioxin-6-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-3,3,3-trifluoropropan-1-one

A mixture of7-benzyl-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-amine(0.742 g, 1.98 mmol), ammonium formate (1.25 g, 19.83 mmol) andpalladium, 10% wt. on activated carbon (75 mg) in methanol (10 mL washeated to 60° C. for 2 h. The mixture was cooled to r.t. and filteredover celite. The filtrate was concentrated under reduced pressure togive a white solid which was dissolved in water. The mixture wasextracted twice with a 3:1 mixture of chloroform:isoproanol. Thecombined organic extracts were dried over sodium sulfate andconcentrated to dryness to give 0.55 g (98%) of a white solid. The solid(0.240 g, 0.84 mmol) was dissolved in DMF (5 mL). To the solution wasadded 3,3,3-trifluoropropanoic acid (0.10 mL 1.10 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.21 g,1.10 mmol), 1-hydroxybenzotriazole (0.148 g, 1.10 mmol) andN,N-diisopropylethylamine (0.37 mL 2.11 mmol). The mixture was stirredat r.t. for 16 h and poured into water (50 mL). The mixture wasextracted with ethyl acetate (50 mL). The organic layer was washed withsaturated aqueous sodium bicarbonate, water and brine and dried overmagnesium sulfate. The solvent was concentrated to leave an oil whichwas purified by silica gel chromatography (ethyl acetate/hexanegradient) to give 0.180 g (54%) of the title compound as a white solid.

MS: M+H=395.

C.7-(3,3,3-Trifluoropropyl)-5,6,7,8-tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-aminehydrochloride

A solution of1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-3,3,3-trifluoropropan-1-one(0.069 g, 0.17 mmol) in THF (5 mL) was cooled to 0° C. under nitrogen.Lithium aluminum hydride was added (0.85 ml of a 1.0M solution in THF,0.85 mmol) and the mixture was stirred at 0° C. for one h. The mixturewas allowed to gradually warm to r.t. with overnight stirring and thencooled again to 0° C. Water (1 mL) was added dropwise. After five min,10N NaOH (1 mL) was added and the mixture was allowed to warm to r.t.Water (3 mL) was added. The mixture was then extracted with ethylacetate (2×15 mL). The combined organic extracts were washed with waterand brine and dried over sodium sulfate. The solvent was concentrated toleave an oil which was purified by silica gel chromatography (ethylacetate/hexane gradient). The colorless oil so obtained (0.020 g) wasdissolved in diethyl ether and treated with 1.0 M HCl in diethyl ether(0.05 mL) to produce a solid which was triturated with diethyl ether anddried to yield the product (17 mg).

MS: M+H=381. ¹H NMR (DMSO-d6): δ 2.90-3.10 (m, 4H), 3.42-3.48 (m, 2H),4.20-4.90 (m, 8H), 6.85 (d, 8.4 Hz, 1H), 7.04 (dd, 8.4 Hz, 2.5 Hz, 1H),7.19 (d, 2.5 Hz, 1H), 8.52 (s, 1H), 9.08 (brs, 0.8H),

Example 8(4-tert-Butyl-phenyl)-[7-(3-methanesulfonyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine

A mixture ofN-(4-tert-butylphenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineprepared as described in Example 3.A. (0.066 g, 0.23 mmol),2-chloro-3-(methylsulfonyl)pyridine (Ponticello et al, J. Org. Chem.,44(17), 1979), (0.088 g, 0.47 mmol) and N,N-diisopropylethlamine (0.041mL, 0.23 mmol) was heated in a sealed tube via microwave (EmrysOptimizer model, Personal Chemistry) for 30 min at 150° C. The reactionmixture was cooled to r.t. and poured into water (20 mL). The mixturewas extracted with ethyl acetate (2×20 mL). The combined organic layerswere washed with brine, dried over magnesium sulfate and concentrated toleave an oil which was purified by silica gel chromatography (ethylacetate/hexane gradient) to give the title compound as a white solid(0.049 g, 48%).

MS: M+H=438. ¹H NMR (DMSO-d6): δ 1.29 (s, 9H), 2.82 (t, 5.7 Hz, 2H),3.32 (s, 3H), 3.57 (t, 5.7 Hz, 2H), 4.31 (s, 2H), 7.34 (d, 8.7 Hz, 2H),7.43 (dd, 7.9 Hz, 4.7 Hz, 1H), 7.59 (d, 8.7 Hz, 2H), 8.34 (dd, 7.9 Hz,1.8 Hz, 1H), 8.37 (s, 1H), 8.48 (s, 1H), 8.66 (dd, 4.7 Hz, 1.8 Hz, 1H).

Example 9[7-(3-Methanesulfonyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineprepared as described in Example 1.D. (0.100 g, 0.34 mmol) was dissolvedin a mixture of dioxane/N,N-dimethylacetamide (10:1) (1.1 mL). To thesolution was added 2-chloro-3-(methylsulfonyl)pyridine (Ponticello etal, J. Org. Chem., 44(17), 1979) (0.128 mg, 0.67 mmol) andN,N-diisopropylethylamine (0.09 mL, 0.51 mmol). The mixture was heatedvia microwave (Emrys Optimizer model, Personal Chemistry) at 150° C. for20 min. The reaction mixture was poured into water (20 mL) and extractedwith ethyl acetate (2×20 mL). The combined organic layers were washedwith brine, dried over magnesium sulfate, and concentrated to leave asolid. The solid was purified by silica gel chromatography using agradient of ethyl acetate:hexane (0-100%) to give the desired compoundas an white solid (75 mg, 49%).

MS: M+H=450. ¹H NMR (DMSO-d6): δ 2.90 (t, 5.6 Hz, 2H), 3.32 (s, 3H),3.58 (t, 5.6 Hz, 2H), 4.36 (s, 2H), 4.44 (dd, 7.9 Hz, 4.7 Hz, 1H), 7.68(d, 8.7 Hz, 2H), 8.02 (d, 8.7 Hz, 2H), 8.35 (dd, 7.9 Hz, 1.9 Hz, 1H),8.52 (s, 1H), 8.67 (dd, 4.7 Hz, 1.9 Hz, 1H), 8.86 (s, 1H).

Example 107-(3-(Ethylsulfonyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A. 2-Chloro-3-(ethylsulfonyl)pyridine

2-Chloropyridin-3-amine (6.1 g, 48 mmol) was dissolved in ethanol (40mL) and HBF₄ (20 mL, 50%) was added at 0° C. After stirring for 5 min, asolution of NaNO₂ (3.5 g) in water (20 mL) was added dropwise mantaininga temperature of <5° C. Ether was then added and the salts wereprecipitated, filtered and rinsed with ether to give pink crystals (8.6g, 82%). The crystals were dissolved in acetonitrile at 0° C. and sodiumethanthiolate was added (50 mmol, 4.2 g) and stirred for 24 h. Thesolvent was evaporated after filtration and the residue was purified byHPLC to give the material as an orange solid (0.8 g, 10%). The materialwas then dissolved in chloroform (30 mL) and m-CPBA (3.2 g, 9.3 mmol)was added and the mixture was stirred overnight. The solution wasneutralized with NaHCO₃ and the organic layer was dried over Na₂SO₄,filtered and evaporated to give the product as an off-white powder (0.5g, 51%).

MS: M+H=206.

B.7-(3-(Ethylsulfonyl)pyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 9 usingN-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineprepared as described in Example 1.D. (0.100 g, 0.34 mmol),2-chloro-3-(ethylsulfonyl)pyridine (0.140 g, 0.68 mmol) andN,N-diisopropylethylamine (0.09 mL, 0.51 mmol) to obtain 0.062 g of awhite solid.

MS: M+H=464. ¹H NMR (DMSO-d6): δ 0.98 (t, 7.4 Hz, 3H), 2.89 (t, 5.6 Hz,2H), 3.50 (q, 7.4 Hz, 2H), 3.59 (t, 5.6 Hz, 2H), 4.36 (s, 2H), 7.44 (dd,7.8 Hz, 4.7 Hz, 1H), 7.68 (d, 8.7 Hz, 2H), 8.02 (d, 8.7 Hz, 2H), 8.33(dd, 7.8 Hz, 1.8 Hz, 1H), 8.52 (s, 1H), 8.67 (dd, 4.7 Hz, 1.8 Hz, 1H),8.87 (s, 1H).

Example 11[7-(3-Fluoro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared according to the procedure given forExample 9 usingN-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineprepared as described in Example 1.D. (0.15 g, 0.51 mmol),2-chloro-3-fluoropyridine (0.134 g, 0.10 mmol),N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reactionmixture 9 h at 170° C. to obtain 0.062 g of a white solid.

MS: M+H=390.

Example 12(4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine

The title compound was prepared according to the procedure given forExample 9 usingN-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineprepared as described in Example 1.D. (0.150 g, 0.51 mmol),2-chloro-3-(trifluoromethyl)pyridine (0.185 g, 0.10 mmol),N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reactionmixture 6 h at 180° C. to obtain 0.130 g of a light yellow solid.

MS: M+H=440. ¹H NMR (DMSO-d6): δ 2.85 (t, 5.8 Hz, 2H), 3.61 (t, 5.8 Hz,2H), 4.36 (s, 2H), 7.22 (dd, 7.8 Hz, 4.9 Hz, 1H), 7.68 (d, 8.7 Hz, 2H),7.99 (d, 8.7 Hz, 2H), 8.12 (dd, 7.8 Hz, 1.7 Hz, 1H), 8.51 (s, 1H), 8.55(dd, 4.9 Hz, 1.7 Hz, 1H), 8.82 (s, 1H).

Example 13(4-tert-Butyl-phenyl)-[7-(3-chloro-pyridin-2-yl)-2-morpholin-4-ylmethyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-amine

A. 2-Morpholinoethane-1,1-diamine

Sodium hydride (2.4 g, 60 mmol, 60%) was added to the solution ofmorpholine (5.2 g, 60 mmol) in THF (40 mL, anhydrous) and stirred for 30min at room temperature under nitrogen. Chloroacetamidine hydrochloride(2.58 g, 20 mmol) was added to this solution in one portion and stirredat 50° C. overnight. Solvent was removed under reduced pressure and thedark brown oily residue was directly used in the next step.

B.7-Benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4(4aH)-one

Ethyl N-benzyl-3-oxo-4-piperidinecarboxylate hydrochloride (2.98 g, 10mmol) and 2-Morpholinoethane-1,1-diamine (˜20 mmol) were dissolved inthe solution of sodium methoxide in methanol (12 mL, 25% wt) and stirredat 100° C. in a sealed tube for 4 h. Solvent was removed in vacuo,residue was dissolved in water (100 mL) and was extracted by CHCl₃ andi-PrOH (3:1, 5×80 mL), dried over sodium sulfate. Solvent was removed invacuo, brown solid residue was directly gone to next step.

MS: 341.4

C.7-Benzyl-4-chloro-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidine

N,N-Dimethylaniline (1.2 g, 10 mmol) and phosphorus oxychloride (12.2 g,80 mmol) were added to the solution of7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4(4aH)-one(˜10 mmol) in 1,2-dichloroethane (30 mL, anhydrous) and were stirred ina preheated oil bath at 90° C. for 30 min. Reaction mixture was pouredinto ice, neutralized by solid sodium bicarbonate, extracted by ethylacetate and dried over sodium sulfate. Solvent was removed in vacuo andbrown oil residue was directly gone to next step.

MS: M+H=359.2.

D.N-(4-tert-Butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine

The solution of7-Benzyl-4-chloro-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidine(358 mg, 1 mmol) and 4-tert-butylaniline (179 mg, 1.2 mmol) inacetonitrile (2 mL) was irradiated in microwave at 180° C. for 5 min.Solvent was removed and the residue was dissolved in water, extracted byethyl acetate, dried over sodium sulfate and purified by columnchromatography. Product was obtained as a white foam (120 mg, 25%).

MS: M+H=372.1.

E.N-(4-tert-Butylphenyl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine

Catalytic amount palladium hydroxide on carbon powder (20% Pd, moistureea. 60%) was added to the solution ofN-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine(240 mg, 0.51 mmol) in methanol and was stirred at hydrogen atmosphereover night at room temperature. Reaction solution was filtered throughcelite and filtrate was concentrated to yield the product as a whitepowder (150 mg, 77%).

MS: M+H=382.3.

F.N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine

The solution of diisopropylethylamine (35 mg, 0.27 mmol),N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(morpholinomethyl)pyrido[3,4-d]pyrimidin-4-amine(70 mg, 0.18 mmol) and 2,3-dichloropyridine (54 mg, 0.36 mmol) indioxane (2 mL) and N,N-diethylacetamide (0.2 mL) was irradiated inmicrowave at 180° C. for 10 hr. Solvent was removed in vacuo and residuewas purified by column chromatography, product was obtained as a lightyellow foam (27 mg, 31%).

MS: M+H=493.5. ¹H NMR CDCl₃ δ: 1.33 (s, 9H), 2.67-2.69 (m, 4H),2.76-2.79 (m, 2H), 3.69 (s, 2H), 3.76-3.80 (m, 6H), 4.54 (s, 2H), 6.35(br s, 1H), 6.84-6.88 (m, 1H), 7.36-7.38 (m, 2H), 7.57-7.63 (m, 3H),8.18-8.20 (m, 1H).

Example 14N-(4-(Difluoromethoxy)phenyl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine

A.7-Benzyl-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A mixture of 7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidineprepared as described in Example 1.B. (1.09 g, 4.21 mmol) and4-(difluoromethoxy)benzenamine (1.34 g, 8.42 mmol) in 1,4-dioxane (15mL) was heated in a sealed tube at 100° C. for 16 h. The dark slurry wascooled to r.t. and diluted with diethyl ether. The solid was collectedby flitration and triturated with ethyl acetate: hexane (1:9) and driedto give a tan solid (1.3 g, 81%) which was used directly.

MS: M+H=383

B.N-(4-(Difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(1.01 g, 2.65 mmol), ammonium formate (1.67 g, 26.46 mmol) andpalladium, 10% wt. on activated carbon (100 mg) in methanol (20 mL) washeated to 60° C. for 1 h. The mixture was cooled to r.t. and filteredover celite. The filtrate was concentrated under reduced pressure togive a white solid which was taken up in saturated aqueous sodiumbicarbonate. The mixture was extracted three times with ethyl acetate.The combined organic extracts were washed with brine, dried over sodiumsulfate and concentrated to dryness to give 0.82 g of a tan solid. Thecompound was further purified by silica gel chromatography using agradient of methanol:chloroform (0-20%) to give the desired compound asan white solid.

MS: M+H=293.

C.N-(4-(Difluoromethoxy)phenyl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 9 usingN-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.088 g, 0.30 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello etal, J. Org. Chem., 44(17), 1979) (0.115 mg, 0.60 mmol) andN,N-diisopropylethylamine (0.079 mL, 0.45 mmol) to obtain 0.085 g oftitle compound as a light yellow solid.

MS: M+H=448. ¹H NMR (DMSO-d6): δ 2.93 (t, 5.8 Hz, 2H), 3.33 (s, 3H),3.51 (t, 5.8 Hz, 2H), 4.31 (s, 2H), 7.12 (d, 8.9 Hz, 2H), 7.15 (t, 75Hz, 1H), 7.51 (dd, 7.9 Hz, 4.9 Hz, 1H), 7.68 (d, 8.9 Hz, 2H), 8.36 (dd,7.9 Hz, 1.8 Hz, 1H), 8.42 (s, 1H), 8.56 (s, 1H), 8.74 (dd, 4.9 Hz, 1.8Hz, 1H).

Example 157-(3-Chloropyridin-2-yl)-N-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 9 usingN-(4-(difluoromethoxy)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.091 g, 0.31 mmol), 2,3-dichloropyridine (0.092 g, 0.62 mmol) andN,N-diisopropylethylamine (0.081 mL, 0.47 mmol) and heating the reactionmixture for 10 h at 170° C. to obtain 0.038 g of a light yellow solid.

MS: M+H=404. ¹H NMR (DMSO-d6): δ 2.89 (t, 5.8 Hz, 2H), 3.62 (t, 5.8 Hz,2H), 4.38 (s, 2H), 7.07 (dd, 7.8 Hz, 4.8 Hz, 1H), 7.14 (d, 9.0 Hz, 2H),7.16 (t, 75 Hz, 1H), 7.67 (d, 9.0 Hz, 2H), 7.89 (dd, 7.8 Hz, 1.6 Hz,1H), 8.28 (dd, 4.8 Hz, 1.6 Hz, 1H), 8.39 (s, 1H), 8.65 (s, 1H).

Example 16N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-(3-(isopropylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine

A. 2-Chloro-3-(isopropylsulfonyl)pyridine

2-Chloropyridin-3-amine (6.1 g, 48 mmol) was dissolved in ethanol (40mL) and HBF₄ (20 mL, 50%) was added at 0° C. After stirring for 5 min, asolution of NaNO₂ (3.5 g) in water (20 mL) was added dropwisemaintaining a temperature of <5° C. Ether was then added and the saltswere precipitated, filtered and rinsed with ether to give pink crystals(8.6 g, 82%). The crystals were dissolved in acetonitrile at 0° C. andsodium 2-propanethiolate (4.9 g, 50 mmol) was added and stirred for 24h. The solvent was evaporated after filtration and the residue waspurified by HPLC to give the material as an orange solid (0.98 g, 11%).The material was then dissolved in chloroform (30 mL) and mCPBA (3.7 g,10.6 mmol) was added and the mixture was stirred overnight. The solutionwas neutralized with NaHCO₃ and the organic layer was dried over Na₂SO₄,filtered and evaporated to give the product as an off-white powder (0.7g, 59%).

MS: M+H=220.

B.N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-(3-(isopropylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 9 usingN-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amineprepared as described in Example 1.D. (0.073 g, 0.25 mmol),2-chloro-3-(isopropylsulfonyl)pyridine (0.070 g, 0.32 mmol) andN,N-diisopropylethylamine (0.082 mL, 0.47 mmol) to obtain 0.073 g of awhite solid.

MS: M+H=478. ¹H NMR (DMSO-d6): δ 1.06 (d, 6.9 Hz, 6H), 2.88 (t, 5.8 Hz,2H), 3.58 (t, 5.8 Hz, 2H), 3.94 (heptet, 6.9 Hz, 1H), 4.36 (s, 2H), 7.44(dd, 7.8 Hz, 4.7 Hz, 1H), 7.68 (d, 8.6 Hz, 2H), 8.03 (d, 8.6 Hz, 2H),8.33 (dd, 7.8 Hz, 1.8 Hz, 1H), 8.52 (s, 1H), 8.67 (dd, 4.7 Hz, 1.8 Hz,1H), 8.87 (s, 1H).

Example 177-(3-Chloro-pyridin-2-yl)-N⁴-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine-2,4-diamine

A. 2-Amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one

The suspension of ethyl N-benzyl-3-oxo-4-piperidine-carboxylatehydrochloride (2.98 g, 10 mmol) and guanidine hydrochloride (1.15 g, 12mmol) in the solution of sodium methoxide in methanol (11.5 mL, 25% wt)was stirred at 100° C. in a sealed tube overnight before solvent wasremoved in vacuo. Residue was dissolved in water (10 mL) and wasextracted by CHCl₃ and i-PrOH (3:1, 5×80 mL), dried over sodium sulfate.Solvent was removed in vacuo, product was obtained as a light yellowpowder (2.45 g, 96%).

MS: M+H=257.2

B. 2-Benzyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-amine

N,N-Dimethylaniline (1.4 g, 11.4 mmol) and phosphorus oxychloride (14 g,91.2 mmol) were added to the solution of2-amino-7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(4aH)-one(2.9 g, 11.4 mmol) in 1,2-dichloroethane (23 mL, anhydrous) and werestirred in a preheated oil bath at 90° C. for 45 min. The reactionmixture was poured into ice, neutralized by solid sodium carbonate,extracted by ethyl acetate, and the dark brown semi solid was dissolvedin methanol. The combined ethyl acetate and methanol solution was driedover sodium sulfate. Solvent was removed in vacuo and product wasobtained as a light brown solid (2.6 g, 83%).

MS: M+H=275.2.

C.2-Benzyl-N⁵-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-5,7-diamine

Sodium iodide (252 mg, 1.68 mmol) and hydriodic acid (1 mL, 47% aqueoussolution) were added to the solution of2-benzyl-5-chloro-1,2,3,4-tetrahydroisoquinolin-7-amine (380 mg, 1.4mmol) and 4-aminobenzotrifluoride (446 mg, 2.8 mmol) in dioxane (10 mL)and the reaction solution was stirred at 100° C. over night beforesolvent was removed in vacuo. Residue was dissolved in ethyl acetate,washed by water, brine, dried over sodium sulfate and was purified bycolumn chromatography. Product was obtained as brown oil (440 mg, 79%).

MS: M+H=400.2.

D.N⁵-(4-(Trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-5,7-diamine

1-Chloroethyl chloroformate (864 mg, 6 mmol) was added dropwise to thesolution of2-benzyl-N⁵-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-5,7-diamine(1.2 g, 3 mmol) and diisopropylethyl amine (774 mg, 6 mmol) in1,2-dichloroethane (30 mL, anhydrous) at 0° C. After addition, thereaction mixture was stirred at room temperature for 1 hr. Solvent wasremoved in vacuo, residue was dissolved in methanol (10 mL) and wasstirred at room temperature for 10 h. Solvent was removed in vacuo andsolid residue was washed by diethyl ether. Product was obtained as alight brown solid (834 mg, 90%).

MS: M+H=310.2.

E.7-(3-Chloropyridin-2-yl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

The solution of diisopropylethylamine (97 mg, 0.75 mmol),N⁵-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-5,7-diamine(155 mg, 0.5 mmol) and 2,3-dichloropyridine (148 mg, 1.0 mmol) indioxane (2 mL) and N,N-diethylacetamide (0.2 mL) was irradiated inmicrowave at 180° C. for 10 hr. Solvent was removed in vacuo and residuewas purified by column chromatography, product was obtained as a lightorange solid (10 mg, 5%).

MS: M+H=421.4. ¹H NMR CDCl₃ δ: 2.72 (t, J=6.0 Hz, 2H), 3.77 (t, J=6.0Hz, 2H), 4.39 (s, 2H), 4.77 (br s, 2H), 6.45 (br s, 1H), 6.84-6.88 (m,1H), 7.56-7.63 (m, 3H), 7.74-7.76 (m, 2H), 8.18-8.20 (m, 1H).

Example 187-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine

A. 7-Benzyl-5,6,7,8-tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine prepared asdescribed in Example 1.B. (1.0 g, 3.86 mmol) was dissolved in anhydrousacetonitrile (3 mL) and aniline was added (0.39 mL, 4.24 mmol). Themixture was heated at 180° C. for 600 s in a microwave (Emrys Optimizermodel, Personal Chemistry). The solvents were removed under vacuum togive the desired product as a beige powder (1.5 g, quant.). The crudeproduct was used for the subsequent step.

MS: M+H=317.

B. 5,6,7,8-Tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-5,6,7,8-tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine (1.5g, 3.8 mmol) was dissolved in methanol (25 mL) and palladium hydroxidewas added (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker underH₂(g) atmosphere (60 PSI) for 1 day. The mixture was filtered throughcelite and evaporated to give 0.95 g of material as a yellow solid(quant.), which was used as such for the next step.

MS: M+H=227.

C.7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine

5,6,7,8-Tetrahydro-N-phenylpyrido[3,4-d]pyrimidin-4-amine (500 mg, 2.2mmol) was dissoled in a mixture of dioxane/N,N-dimethylacetamide (4:1)(2 mL). To the mixture was added 2,3-dichloropyridine (423 mg, 2.86mmol) and N,N-diisopropylethylamine (0.38 mL, 2.2 mmol). The mixture washeated at 150° C. in a microwave (Emrys Optimizer model, PersonalChemistry) for 16 h. The solvents were removed under vacuum and theresidue was dissolved in ethyl acetate and washed with sat. NaHCO₃ andbrine. The organic layer was dried over Na₂SO₄, filtered and evaporatedto give a brown residue. The residue was purified using a gradient ofethyl acetate:hexane (0-100%) to give the desired compound as anoff-white powder (190 mg, 27%).

MS: M+H=338. ¹H NMR (DMSO-d6): δ 2.88 (t, 5.8 Hz, 2H); 3.62 (t, 5.8 Hz,2H); 4.39 (s, 2H); 7.03-7.10 (m, 2H); 7.28-7.34 (m, 2H); 7.63-7.67 (m,2H); 7.88 (dd, 7.8 Hz, 1.7 Hz, 1H); 8.28 (dd, 4.8 Hz, 1.7 Hz, 1H); 8.40(s, 1H); 8.58 (s, 1H).

Example 197-(3-Chloropyridin-2-yl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A.7-Benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (0.25 g,0.97 mmol) was dissolved in anhydrous acetonitrile (3 mL) and4-fluorobenzenamine was added (0.10 mL, 1.06 mmol). The mixture washeated at 200° C. for 600 s in a microwave (Emrys Optimizer model,Personal Chemistry). The solvents were removed under vacuum to give thedesired product as a beige powder (0.313 g, 97%.). The crude product wasused for the subsequent step.

MS: M+H=335.

B. N-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.64 g, 1.9 mmol) was dissolved in methanol (25 mL) and palladiumhydroxide was added (0.5 g, 20% wt). The mixture was shaken on a ParrShaker under H₂(g) atmosphere (60 PSI) for 1 day. The mixture wasfiltered through celite and evaporated to give 0.47 g of material asgrey crystals (quant.), which was used as such for the next step.

MS: M+H=245.

C.7-(3-Chloropyridin-2-yl)-N-(4-fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

N-(4-Fluorophenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(0.47 g, 1.92 mmol) was dissolved in a mixture ofdioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added2,3-dichloropyridine (420 mg, 2.86 mmol) and N,N-diisopropylethylamine(0.38 mL, 2.2 mmol). The mixture was heated at 150° C. in a PersonalChemistry microwave for 16 h. The solvents were removed under vacuum andthe residue was dissolved in ethyl acetate and washed with sat. NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered andevaporated to give a brown residue. The residue was purified by silicagel chromatography using a gradient of ethyl acetate:hexane (0-100%) togive the desired compound as an off-white powder (200 mg, 30%).

MS: M+H=356. ¹H NMR (DMSO-d6): δ 2.88 (t, 5.4 Hz, 2H); 3.61 (t, 5.4 Hz,2H); 4.38 (s, 2H); 7.08 (dd, 7.8 Hz, 4.7 Hz, 1H); 7.12-7.19 (m, 2H);7.61-7.67 (m, 2H); 7.89 (dd, 7.8 Hz, 1.4 Hz, 1H); 8.28 (dd, 4.7 Hz, 1.4Hz, 1H); 8.38 (s, 1H); 8.62 (s, 1H).

Example 207-(3-Chloropyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

A.7-Benzyl-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.5 g, 1.93mmol) was dissolved in anhydrous dioxane (3 mL) and6-Trifluoromethylpyridin-3-ylamine was added (469 mg, 2.9 mmol),followed by HI/H₂O (0.3 mL, 47%). The mixture was heated at 130° C. for600 s in a Personal Chemistry microwave. The solvents were removed undervacuum and the residue was dissolved in ethyl acetate and washed withsat. NaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filteredand evaporated to give the product as an orange solid (700 mg, 95%crude). The crude product was used for the subsequent step.

MS: M+H=386.

B.N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(1.7 g, 4.4 mmol) was dissolved in methanol (25 mL) and palladiumhydroxide was added (0.2 g, 20% wt). The mixture was shaken on a ParrShaker under H₂(g) atmosphere (60 PSI) for 1 day. The mixture wasfiltered through celite and evaporated to give 1.3 g (quant.) as anorange oil, which was used as such for the next step.

MS: M+H=296.

C.7-(3-Chloropyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(130 mg, 0.44 mmol) was dissolved in a mixture ofdioxane/N,N-dimethylacetamide (4:1) (2 mL). To the mixture was added2,3-dichloropyridine (98 mg, 0.66 mmol) and N,N-diisopropylethylamine(0.1 mL, 0.66 mmol). The mixture was heated at 150° C. in a PersonalChemistry microwave for 16 h. The solvents were removed under vacuum andthe residue was dissolved in ethyl acetate and washed with sat. NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered andevaporated to give a brown residue. The residue was purified using agradient of ethyl acetate: hexane (0-100%) to give the desired compoundas an off-white powder (50 mg, 28%).

MS: M+H=407. ¹H NMR (DMSO-d6): δ 2.95 (t, 5.6 Hz, 2H); 3.63 (t, 5.6 Hz,2H); 4.45 (s, 2H); 7.09 (dd, 7.8 Hz, 4.6 Hz, 1H); 7.85 (d, 8.7 Hz, 1H);7.90 (dd, 7.8 Hz, 1.6 Hz, 1H); 8.29 (dd, 4.6 Hz, 1.6 Hz, 1H); 8.44 (dd,8.7 Hz, 2.4 Hz, 1H); 8.54 (s, 1H); 9.05 (d, 2.4 Hz, 1H); 9.15 (s, 1H).

Example 21N-(6-(Trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given inExample 20.C. usingN-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(140 mg, 0.47 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello,JOC, 44(17), 1979) (0.115 g, 0.06 mmol) and N,N-diisopropylethylamine(0.17 mL, 0.98 mmol) to give the desired compound as an off-white powder(55 mg, 26%).

MS: M+H=451. ¹H NMR (DMSO-d6): δ 2.99 (t, 5.7 Hz, 2H); 3.53 (t, 5.7 Hz,2H); 3.33 (s, 3H); 4.39 (s, 2H); 7.52 (dd, 7.8 Hz, 4.7 Hz, 1H); 7.85 (d,8.7 Hz, 1H); 8.37 (dd, 7.8 Hz, 1.9 Hz, 1H); 8.46 (dd, 8.7 Hz, 2.3 Hz,1H); 8.56 (s, 1H); 8.74 (dd, 4.7 Hz, 1.9 Hz, 1H); 9.04 (d, 2.3 Hz, 1H),9.07 (s, 1H).

Example 227-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine

A.7-Benzyl-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared substantially according to the proceduregiven for Example 20.A, using7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine (0.2 g, 0.77mmol), and 4-(trifluorosulphonyl)aniline (0.27 g, 1.2 mmol) to give thedesired compound as a brown solid (278 mg. 82%).

MS: M+H=449.

B.5,6,7,8-Tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine

7-Benzyl-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine(270 mg, 0.55 mmol) was dissolved in anhydrous chloroform (10 mL) and1-chloroethylchloroformate was added (0.18 mL, 1.65 mmol). Afterstirring for 30 min, N,N-diisopropylethylamine was added (0.24 mL, 1.65mmol) and the mixture was stirred for an additional 2 h. The chloroformwas removed under vacuum and 30 ml of methanol was added and the mixturewas heated for 30 min. Upon reaction completion, the methanol wasremoved and the residue was dissolved in ethyl acetate and washed withsat. NaHCO₃ and brine. The organic layer was dried over Na₂SO₄, filteredand evaporated to give the product (163 mg, 83%). The crude material wasused for the next step.

M+H=359.

C.7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 20.C. using5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine(160 mg, 0.45 mmol), 2,3-dichloropyridine (135 mg, 0.9 mmol) andN,N-diisopropylethylamine (0.16 mL, 0.9 mmol) to give the desiredcompound as an off-white powder (40 mg, 19%).

MS: M+H=470.

Example 235,6,7,8-tetrahydro-7-(3-(methylsulfonyl)pyridin-2-yl)-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 20.C. using5,6,7,8-tetrahydro-N-(4-(trifluoromethylsulfonyl)phenyl)pyrido[3,4-d]pyrimidin-4-amine(308 mg, 0.86 mmol), 2-chloro-3-(methylsulfonyl)pyridine (Ponticello,JOC, 44(17), 1979) (0.200 g, 1.04 mmol) and N,N-diisopropylethylamine(0.25 ml, 1.43 mmol) to give the desired compound as an off-white powder(75 mg, 19%).

MS: M+H=450. ¹H NMR (DMSO-d6): δ 3.0 (t, 5.6 Hz, 2H); 3.31 (s, 3H); 3.53(t, 5.6 Hz, 2H); 4.41 (s, 2H), 7.51 (dd, 7.8 Hz, 4.8 Hz, 1H); 8.02 (d,9.0 Hz, 2H); 8.20 (d, 9.0 Hz, 2H); 8.37 (dd, 7.8 Hz, 1.8 Hz, 1H); 8.64(s, 1H); 8.74 (dd, 4.8 Hz; 1.8 Hz, 1H); 9.28 (s, 1H).

Example 24[7-(3-Chloro-pyridin-2-yl)-2-methylsulfanyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine

A.7-Benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4(4aH)-one

The suspension of ethyl N-benzyl-3-oxo-4-piperidine-carboxylatehydrochloride (8.9 g, 30 mmol) and thiourea (4.56 g, 60 mmol) in thesolution of sodium methoxide in methanol (34 mL, 25% wt) was stirred at100° C. in a sealed tube overnight. Iodomethane (5.1 g, 42 mmol) wasadded dropwise to the reaction mixture after cooled to room temperatureand stirred at room temperature for 1 hr. Solvent was removed in vacuoand residue was dissolved in water (100 mL) and was extracted by CHCl₃and i-PrOH (3:1, 10×40 mL), dried over sodium sulfate. Solvent wasremoved in vacuo, product was obtained as a beige powder (7.6 g, 88%).

MS: M+H=287.9.

B.7-Benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine

N,N-Dimethylaniline (3.2 g, 26.6 mmol) and phosphorus oxychloride (32.6g, 213 mmol) were added to the solution of7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4(4aH)-one(7.6 g, 26.6 mmol) in 1,2-dichloroethane (20 mL, anhydrous) and werestirred in a preheated oil bath at 90° C. for 1 hr. Reaction mixture waspoured into ice, neutralized by solid sodium carbonate, extracted byethyl acetate and dried over sodium sulfate. Solvent was removed invacuo and light brown oil residue was directly gone to next step.

MS: M+H=307.1.

C.7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

Sodium iodide (3.9 g, 26 mmol) and hydriodic acid (10 mL, 47% aqueoussolution) were added to the solution of7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine(8.0 g, 26 mmol) and 4-aminobenzotrifluoride (5.06 g, 0.031 mol) indioxane (100 mL) and the reaction solution was stirred at 100° C.overnight. Solid thus formed was filtered out, washed by ethyl acetateand diethyl ether and dried in vacuo. Product was obtained as whiteneedle solid (8.2 g, 73%).

MS: M+H=431.7.

D.N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

1-Chloroethyl chloroformate (572 mg, 4 mmol) was added dropwise to thesolution of7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine(860 mg, 2 mmol) and diisopropylethyl amine (516 mg, 4 mmol) in1,2-dichloroethane (5 mL, anhydrous) at 0° C. After addition, thereaction mixture was stirred at room temperature for 1 hr. Solvent wasremoved in vacuo, residue was dissolved in methanol (10 mL) and wasstirred at room temperature overnight. Solvent was removed in vacuo,residue was dissolved in ethyl acetate and was washed by sodiumbicarbonate's aqueous solution, brine and dried over sodium sulfate.Solvent was removed in vacuo and residue was triturated by diethyl etherto yield the product as a beige solid (454 mg, 67%).

MS: M+H=340.7.

E.7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

The solution of diisopropylethylamine (252 mg, 1.95 mmol),N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine(443 mg, 1.3 mmol) and 2,3-dichloropyridine (386 mg, 2.6 mmol) indioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was irradiated inmicrowave at 180° C. for 10 h. Solvent was removed in vacuo and residuewas purified by column chromatography, product was obtained as a beigesolid (100 mg, 17%).

MS: M+H=452.0. ¹H NMR DMSO-d₆ δ: 2.45 (s, 3H), 2.78 (t, J=5.6 Hz, 2H),3.68 (t, J=5.6 Hz, 2H), 4.34 (s, 2H), 7.02-7.05 (m, 1H), 7.68-7.70 (m,2H), 7.85-7.87 (m, 1H), 7.94-7.96 (m, 2H), 8.23-8.24 (m, 1H), 8.85 (s,1H).

Example 25[7-(3-Chloro-pyridin-2-yl)-2-methanesulfonyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(4-trifluoromethyl-phenyl)-amine

m-CPBA (148 mg, 0.6 mmol, 70%) was added to the solution of7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-aminefrom Example 24 (92 mg, 0.2 mmol) in ethanol (5 mL) and stirred at roomtemperature for 3 h. Solvent was removed in vacuo, residue was dissolvedin ethyl acetate and was washed by sodium bicarbonate's aqueoussolution, sodium hydrosulfite's aqueous solution and brine, dried oversodium sulfate. After purified by column chromatography, product wasobtained as a white powder (16 mg, 17%).

MS: M+H=484.0. ¹H NMR DMSO-d₆ δ: 2.90 (t, J=5.6 Hz, 2H), 3.30 (s, 3H),3.75 (t, J=5.6 Hz, 2H), 4.50 (s, 2H), 7.04-7.08 (m, 1H), 7.73-7.76 (m,2H), 7.88-7.90 (m, 1H), 7.95-7.97 (m, 2H), 8.24-8.26 (m, 1H), 9.36 (s,1H).

Example 266-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine

A.7-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine

The 2-Benzyl-5-bromo-1,2,3,4-tetrahydro-2,6-naphthyridine (seeWO03/076427) (250 mg, 0.82 mmol) was dissolved in 1 mL of anhydroustoluene. To the mixture was added Pd₂(dba)₃ (10 mol %, 85 mg) andPdCl₂(DPPF) (33 mg, 5 mol %), followed by NaOtBu (118 mg, 1.23 mmol).After mixing for 5 min, 4-(trifluoromethyl)aniline (0.153 mL, 1.23 mmol)was added and the mixture was heated at 160° C. for 1200 s in a PersonalChemistry microwave. The reaction mixture was filtered and the solventwas evaporated and the residue was dissolved in ethyl acetate and washedwith sat. NaHCO₃ and brine. The organic layer was dried over Na₂SO₄,filtered and evaporated to give a brown-purple residue. The residue waspurified using a gradient of ethyl acetate:hexane (0-100%) to give thedesired compound as an off-white powder (288 mg, 92%).

MS: M+H=384.

B.N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine

6-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine(280 mg, 0.73 mmol) was dissolved in methanol (25 mL) and palladiumhydroxide was added (0.2 g, 20% wt). The mixture was shaken on a ParrShaker under H₂(g) atmosphere (60 PSI) for 1 day. The mixture wasfiltered through celite and evaporated to give 0.21 g of material asgrey crystals (quant.), which was used as such for the next step.

MS: M+H=294.

C.6-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine(200 mg, 0.68 mmol) was dissolved in a mixture ofdioxane/N,N-dimethylacetamide (4:1) (3 mL). To the mixture was added2,3-dichloropyridine (200 mg, 1.36 mmol) and N,N-diisopropylethylamine(0.24 mL, 1.36 mmol). The mixture was heated at 150° C. in a PersonalChemistry microwave for 16 h. The solvents were removed under vacuum andthe residue was dissolved in ethyl acetate and washed with sat. NaHCO₃and brine. The organic layer was dried over Na₂SO₄, filtered andevaporated to give a brown residue. The residue was purified using agradient of ethyl acetate:hexane (0-100%) to give the desired compoundas an off-white powder (76 mg, 27%).

MS: M+H=405.

Example 277-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-methoxypyrido[3,4-d]pyrimidin-4-amine

Sodium methoxide (16 mg, 0.3 mmol) was added to the suspension of7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-aminefrom Example 25 (100 mg, 0.2 mmol) in methanol (5 mL, anhydrous) andstirred at 60° C. overnight. Solvent was removed in vacuo, residue wasdissolved in ethyl acetate and washed by water, brine, dried over sodiumsulfate. After concentration, solid residue was triturated by diethylether to yield the product as a white powder (70 mg, 81%).

MS: M+H=435.8. ¹H NMR DMSO-d₆ δ: 2.78 (t, J=5.6 Hz, 2H), 3.68 (t, J=5.6Hz, 2H), 3.84 (s, 3H), 4.32 (s, 2H), 7.01-7.04 (m, 1H), 7.67-7.69 (m,2H), 7.84-7.87 (m, 1H), 8.00-8.02 (m, 2H), 8.22-8.23 (m, 1H), 8.83 (s,1H).

Example 28N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

A.N-(4-tert-Butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

The solution of7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidine(915 mg, 3 mmol) from Example 24. B. and 4-tert-butylaniline (537 mg,3.6 mmol) in acetonitrile (5 mL) was irradiated in microwave at 180° C.for 10 min. Solid thus formed was filtered out and washed by hexanes.Product was obtained as a light brown solid (750 mg, 60%).

MS: M+H=418.9.

B.N-(4-tert-Butylphenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

1-Chloroethyl chloroformate (732 mg, 5.12 mmol) was added dropwise tothe solution ofN-(4-tert-butylphenyl)-7-benzyl-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine(1.07 g, 2.56 mmol) and diisopropylethyl amine (660 mg, 5.12 mmol) in1,2-dichloroethane (10 mL, anhydrous) at 0° C. After addition, thereaction mixture was stirred at room temperature for 1 hr. Solvent wasremoved in vacuo, residue was dissolved in methanol (10 mL) and wasstirred at room temperature overnight. Solvent was removed in vacuo,residue was dissolved in ethyl acetate and was washed by sodiumbicarbonate's aqueous solution, brine and dried over sodium sulfate.Solvent was removed in vacuo and residue was triturated by diethyl etherto yield the product as a light brown solid (303 mg, 36%).

MS: M+H=329.4.

C.N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine

The solution of diisopropylethylamine (235 mg, 1.82 mmol),N-(4-tert-butylphenyl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-amine(300 mg, 0.91 mmol) and 2,3-dichloropyridine (270 mg, 1.82 mmol) indioxane (5 mL) and N,N-diethylacetamide (0.5 mL) was irradiated inmicrowave at 180° C. for 10 hr. Solvent was removed in vacuo and residuewas dissolved in ethyl acetate, washed by water, brine, dried oversodium sulfate and purified by column chromatography, product wasobtained as a beige solid (100 mg, 25%).

MS: M+H=439.9. ¹H NMR DMSO-d₆ δ: 1.28 (s, 9H), 2.43 (s, 3H), 2.73 (t,J=5.6 Hz, 2H), 3.67 (t, J=5.6 Hz, 2H), 4.30 (s, 2H), 7.01-7.04 (m, 1H),7.33-7.35 (m, 2H), 7.60-7.62 (m, 2H), 7.84-7.86 (m, 1H), 8.22-8.24 (m,1H), 8.46 (s, 1H).

Example 29N-(4-tert-Butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-methoxypyrido[3,4-d]pyrimidin-4-amine

m-CPBA (148 mg, 0.6 mmol) was added to the solution ofN-(4-tert-butylphenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-2-(methylthio)pyrido[3,4-d]pyrimidin-4-aminefrom Example 28.C. (88 mg, 0.2 mmol) in ethanol (7 mL) and stirred atroom temperature for 1 hr. Solid thus formed was filtered out and driedin vacuo (50 mg). This solid was suspended in methanol (5 mL) and sodiummethoxide (9 mg, 0.165 mmol) was added and stirred at 60° C. overnight.Solvent was removed in vacuo and residue was dissolved in ethyl acetate,washed by water, sodium hydrosulfite aqueous solution, brine and driedover sodium sulfate. Purified by column to yield the product as a whitesolid (33 mg, 39%).

MS: M+H=424.1. ¹H NMR DMSO-d₆ δ: 1.28 (s, 9H), 2.72 (t, J=5.6 Hz, 2H),3.67 (t, J=5.6 Hz, 2H), 3.79 (s, 3H), 4.28 (s, 2H), 7.01-7.02 (m, 1H),7.33-7.35 (m, 2H), 7.62-7.64 (m, 2H), 7.84-7.86 (m, 1H), 8.22-8.24 (m,1H), 8.44 (s, 1H).

Example 30(7-Benzyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amine

The title compound was prepared as described in Example 7A. ¹H NMR(DMSO-d6): δ 2.90 (brs, 2H); 3.3-3.60 (m, 4H); 4.01 (brs, 2H); 4.20(brs, 2H), 4.40 (brs, 2H); 6.82 (d, 8.8 Hz, 1H); 7.06 (dd, 8.8 Hz, 2.5Hz, 1H); 7.22 (d, 2.5 Hz, 1H); 7.46-7.51 (m, 3H); 7.66-7.71 (m, 2H);8.40 (s, 1H); 8.72 (s, 1H).

Example 317-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine

Sodium iodide (720 mg, 4.8 mmol) and hydriodic acid (2.0 mL, 47% aqueoussolution) were added to the solution of7-benzyl-4-chloro-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidineas prepared for Example 5.B. and (1.2 g, 4.0 mmol) and4-aminobenzotrifluoride (1.3 g, 8 mmol) in dioxane (20 mL) and thereaction solution was stirred at 100° C. overnight. Solvent was removedin vacuo and the residue was dissolved in water. Solid sodium carbonatewas added to the solution to a pH>7 then extracted by ethyl acetate.Ethyl acetate phase was washed by brine, and dried over sodium sulfate.Solvent was removed and the residue was purified by columnchromatography to yield the product as a beige solid (910 mg, 54%).

MS: M+H=428.8. ¹H NMR DMSO-d₆ δ: 2.71-2.72 (m, 2H), 2.78-2.79 (m, 2H),3.33 (s, 3H), 3.42 (s, 2H), 3.69 (s, 2H), 4.33 (s, 2H), 7.29-7.30 (m,1H), 7.34-7.37 (m, 4H), 7.65-7.67 (m, 2H), 8.03-8.05 (m, 2H), 8.73 (s,1H).

Example 327-(3-Chloropyridin-2-yl)-N²-(2-(dimethylamino)ethyl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2,4-diamine

The solution of7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-aminefrom Example 25 (50 mg, 0.1 mmol) and unsym-dimethylethylenediamine (100mg, 1.1 mmol) in DMSO was irradiated by microwave at 150° C. for 10 min.The reaction mixture was poured into water and extracted by ethylacetate. Solids between two phases were filtered out and this solid wasdissolved in methanol and undissolved solid was filtered out. Filteratewas concentrated to yield the product as beige powder (20 mg, 41%).

MS: M+H=492.1. ¹H NMR DMSO-d₆ δ: 2.32 (s, 6H), 2.58-2.59 (m, 2H), 2.72(t, J=5.2 Hz, 2H), 3.35-3.41 (m, 2H), 3.63 (t, J=5.6 Hz, 2H), 4.20 (s,2H), 6.56 (br s, 1H), 7.00-7.03 (m, 1H), 7.60-7.62 (m, 2H), 7.83-7.85(m, 1H), 8.02-8.04 (m, 2H), 8.22-8.23 (m, 1H), 8.45 (s, 1H).

Example 337-(3-Chloropyridin-2-yl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-N²-(2-morpholinoethyl)pyrido[3,4-d]pyrimidine-2,4-diamine

The title compound was prepared according to the procedure given forExample 32.

MS: M+H=533.7. ¹H NMR DMSO-d₆ δ: 2.32-2.38 (m, 4H), 2.45-2.47 (m, 2H),2.70-2.73 (m, 2H), 3.34-3.38 (m, 2H), 3.53-3.55 (m, 4H), 3.62-3.64 (m,2H), 4.20 (s, 2H), 6.56 (br s, 1H), 7.00-7.03 (m, 1H), 7.60-7.62 (m,2H), 7.83-7.85 (m, 1H), 8.02-8.04 (m, 2H), 8.22-8.24 (m, 1H), 8.45 (s,1H).

Example 347-(3-Chloropyridin-2-yl)-N⁴-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-N²,N²-dimethylpyrido[3,4-d]pyrimidine-2,4-diamine

The title compound was prepared according to the procedure given forExample 32.

MS: M+H=448.7. ¹H NMR DMSO-d₆ δ: 2.71 (t, J=5.6 Hz, 2H), 3.07 (s, 6H),3.65 (t, J=5.6 Hz, 2H), 4.23 (s, 2H), 6.99-7.02 (m, 1H), 7.63-7.65 (m,2H), 7.82-7.84 (m, 1H), 8.00-8.03 (m, 2H), 8.20-8.22 (m, 1H), 8.49 (s,1H).

Example 357-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine

A.N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine

1-Chloroethyl chloroformate (543 mg, 3.8 mmol) was added dropwise to thesolution of7-benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-aminefrom Example 31 (820 mg, 1.9 mmol) and diisopropylethyl amine (490 mg,3.8 mmol) in 1,2-dichloroethane (5 mL, anhydrous) at room temperature.After addition, the reaction mixture was stirred at 60° C. for 2 h inthe atmosphere of nitrogen. Solvent was removed in vacuo, residue wasdissolved in methanol (10 mL) and was stirred at 60° C. for 1 hr.Solvent was removed in vacuo, residue was dissolved in ethyl acetate andwas washed by sodium bicarbonate aqueous solution, brine and dried oversodium sulfate. Solvent was removed in vacuo and light orange oilyresidue was directly taken to the next step.

MS: M+H=339.0

B.7-(3-Chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine.

The solution of diisopropylethylamine (490 mg, 3.8 mmol),N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methoxymethyl)pyrido[3,4-d]pyrimidin-4-amine(˜1.9 mmol) and 2,3-dichloropyridine (562 mg, 3.8 mmol) in dioxane (5mL) and N,N-diethylacetamide (1.0 mL) was irradiated in microwave at180° C. for 10 h. Solvent was removed in vacuo and residue was purifiedby column chromatography, product was obtained as a beige solid (102 mg,12%).

MS: M+H=450.4. ¹H NMR DMSO-d₆ δ: 2.85 (t, J=5.6 Hz, 2H), 3.38 (s, 3H),3.70 (t, J=5.6 Hz, 2H), 4.37 (s, 2H), 4.39 (s, 2H), 7.02-7.05 (m, 1H),7.66-7.68 (m, 2H), 7.85-7.87 (m, 1H), 8.02-8.07 (m, 2H), 8.23-8.24 (m,1H), 8.82 (s, 1H).

Example 365,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-7-m-tolylpyrido[3,4-d]pyrimidin-4-amine

5,6,7,8-Tetrahydro-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrido[3,4-d]pyrimidin-4-aminefrom Example 7 (110 mg, 0.39 mmol) was dissolved in anhydrous THF (2mL). To the mixture was added m-tolylboronic acid (105 mg, 0.78 mmol),Cu(OAc)₂ (141 mg, 0.78 mmol) and triethylamine (0.68 g, 0.095 mL) and390 mg of crushed, activated 4A moleculer seives. The mixture wasagitated for 6 h and the solvent was removed under vacuum. The residuewas purified using a gradient of ethyl acetate:hexane (0-100%) to givethe desired compound as reddish powder (14 mg, 9.6%).

MS: M+H=375.

Example 374-(4-(Trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-2-carbonitrile

The title compound was prepared according to the procedure given forExample 32.

MS: M+H=430.5. ¹H NMR DMSO-D₆ δ: 2.50 (t, J=5.2 Hz, 2H), 3.71 (t, J=5.2Hz, 2H), 4.44 (s, 2H), 7.05-7.08 (m, 1H), 7.75-7.77 (m, 2H), 7.87-7.90(m, 3H), 8.24-8.26 (m, 1H), 9.29 (s, 1H).

Example 387-Benzyl-5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine

Sodium iodide (434 mg, 2.9 mmol) and hydriodic acid (0.4 mL, 47% aqueoussolution) were added to the solution7-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine pepare as inExample 1 (500 mg, 1.93 mmol) and 3-aminoquinoline (418 mg, 2.9 mmol) indioxane (4 mL) and the reaction solution was treated in a microwave at150° C. for 20 min before solvent was removed. Residue was suspended inwater, solid sodium carbonate was added to a pH>8, extracted by ethylacetate and solvent was removed in vacuo. Residue was purified by columnchromatography to yield the product as a beige solid (405 mg, 58%).

MS: M+H=368.0. ¹H NMR DMSO-d₆ δ: 2.75-2.77 (m, 2H), 2.80-2.83 (m, 2H),3.45 (s, 2H), 3.71 (s, 2H), 7.29-7.31 (m, 1H), 7.34-7.40 (m, 4H),7.54-7.65 (m, 2H), 7.90-7.97 (m, 2H), 8.44 (s, 1H), 8.70 (d, J=2.0 Hz,1H), 8.86 (s, 1H), 9.13 (d, J=2.0 Hz, 1H).

Example 397-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-phenethylpyrido[3,4-d]pyrimidin-4-amine

A. 5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one

7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1.5 g, 6.2mmol) was dissolved in methanol (25 mL) and palladium hydroxide wasadded (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker underH₂(g) atmosphere (60 PSI) for 3 days. The mixture was filtered throughcelite and evaporated to give 0.9 g of material as a yellow solid (96%),which was used as such for the next step.

MS: M+H=152.

B.7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one

5,6,7,8-Tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (600 mg, 4.0 mmol)was dissoled in a mixture of dioxane/N,N-dimethylacetamide (4:1) (2 mL).To the mixture was added 2,3-dichloropyridine (1.8 g, 12.0 mmol) andN,N-diisopropylethylamine (0.7 mL, 4.0 mmol). The mixture was heated at150° C. in a microwave (Emrys Optimizer model, Personal Chemistry) for16 h. The solvents were removed under vacuum and the residue wasdissolved in ethyl acetate and washed with sat. NaHCO₃ and brine. Theorganic layer was dried over Na₂SO₄, filtered and evaporated to give ayellow solid (900 mg, 86%), which was used as such for the next step.

MS: M+H=263.

C.4-Chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine

7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one(900 mg, 3.4 mmol) was dissolved in anhydrous 1,2-dichloroethane (100mL) and stirred under N₂(g) atmosphere. To the mixture was added POCl₃(2.6 mL, 27 mmol), followed by N,N-dimethylaniline (0.44 mL, 3.49 mmol).The mixture was refluxed for 2 h and the solvents were removed undervacuum to give a red residue. The residue was dissolved in 20 ml ofethyl acetate and 20 ml of water was added. The solution was neutralizedwith ice and solid NaHCO₃. After neutralization, ethyl acetate was addedand the organic layer was washed with water and brine. The organic layerwas dried over Na₂SO₄ and the solvents were removed under vacuum. Theresulting red residue was purified using a gradient of ethylacetate:hexane (0-100%) to give the desired compound as yellow crystals(0.31 g, 32%).

MS: M+H=281.

D.7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-phenethylpyrido[3,4-d]pyrimidin-4-amine

A mixture of4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(0.025 g, 0.09 mmol) and 2-phenylethanamine (0.065 mL, 0.51 mmol)) inacetonitrile (1 mL) was heated in a sealed vessel via microwave (EmrysOptimizer model, Personal Chemistry) to 180° C. for 10 min. The reactionmixture was cooled to r.t. and concentrated to dryness. The residue waspurified by silica gel chromatography using a gradient of ethylacetate:hexane (0-100%) to give the desired compound as a white solid(19 mg).

MS: M+H=366.

Example 40N-(4-Chlorophenethyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and starting materialsand heating the reaction mixture for 25 min.

MS: M+H=400.

Example 41N-(4-Chlorobenzyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and startingmaterials.

MS: M+H=386.

Example 42N-(3,4-Dichlorophenyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

Method—The title compound was prepared following the procedure describedabove for Example 39 and adding hydroiodic acid (0.1 mL) and NaI (0.013g, 0.09 mmol) to the reaction mixture and heating for 30 min.

MS: M+H=406.

Example 437-(3-Chloropyridin-2-yl)-N-(3-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and starting materialsand heating the reaction mixture for 60 min.

MS: M+H=406.

Example 44N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-phenylpyrido[3,4-d]pyrimidin-4-amine

The(5,6,7,8-Tetrahydro-pyrido[3,4-d]pyrimidin-4-yl)-(4-trifluoromethylphenyl)amine(100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To themixture was added phenylboronic acid (83 mg, 0.68 mmol), Cu(OAc)₂ (124mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture wasagitated for 6 h and the solvent was removed under the vacuum. Theresidue was purified using a gradient of ethyl acetate: hexane (0-100%)to give the desired compound as reddish powder (8.0 mg, 6.0%).

MS: M+H=385. ¹H NMR (DMSO-d6): δ 2.90 (t, 5.8 Hz, 2H); 3.61 (t, 5.8 Hz,2H); 4.27 (s, 2H); 6.80-6.85 (m, 1H); 7.15-7.20 (m, 2H); 7.26-7.32 (m,2H); 7.71 (d, 8.8 Hz, 2H); 7.96 (d, 8.8 Hz, 2H), 8.50 (s, 1H); 8.82 (s,1H).

Example 45N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-o-tolylpyrido[3,4-d]pyrimidin-4-amine

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To themixture was added o-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)₂ (124mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture wasagitated for 6 h and the solvent was removed under a vacuum. The residuewas purified using a gradient of ethyl acetate:hexane (0-100%) to givethe desired compound as reddish powder (6.0 mg, 5%).

MS: M+H=385.

Example 46N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-m-tolylpyrido[3,4-d]pyrimidin-4-amine

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To themixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)₂ (124mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture wasagitated for 6 h and the solvent was removed under a vacuum. The residuewas purified using a gradient of ethyl acetate:hexane (0-100%) to givethe desired compound as reddish powder (6.2 mg, 5%).

MS: M+H=385. ¹H NMR (DMSO-d6): δ 2.30 (s, 3H); 2.89 (t, 5.6 Hz, 2H);3.58 (t, 5.6 Hz, 2H); 4.25 (s, 2H), 6.65 9d, 7.6 Hz, 1H); 6.94-7.01 (m,2H); 7.14-7.19 (m, 1H); 7.71 (d, 8.8 Hz, 2H), 7.97 (d, 8.8 Hz, 2H); 8.50(s, 1H); 8.81 (s, 1H).

Example 47N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-7-p-tolylpyrido[3,4-d]pyrimidin-4-amine

N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine(100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To themixture was added p-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)₂ (124mg,0.68 mmol) and triethylamine (0.68, 0.095 mL). The mixture wasagitated for 6 h and the solvent was removed under a vacuum. The residuewas purified using a gradient of ethyl acetate:hexane (0-100%) to givethe desired compound as reddish powder (12.8 mg, 10%).

MS: M+H=385. ¹H NMR (DMSO-d6): δ 2.23 (s, 3H); 2.88 (t, 5.7 Hz, 2H);3.54 (t, 5.7 Hz, 2H); 4.21 (s, 2H), 7.07 (d, 9.1 Hz, 2H); 7.10 (d, 9.1Hz, 2H); 7.7 (d, 8.7 Hz, 2H); 7.96 (d, 8.7 Hz, 2H), 8.49 (s, 1H); 8.80(s, 1H).

Example 487-(3-Chloropyridin-2-yl)-2-ethoxy-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared according to the procedure given forExample 27.

MS: M+H=450. ¹H NMR DMSO-d₆ δ: 1.28-1.32 (m, 3H), 2.77 (t, J=5.6 Hz,2H), 3.67 (t, J=5.6 Hz, 2H), 4.24-2.32 (m, 4H), 7.01-7.05 (m, 1H),7.68-7.70 (m, 2H), 7.85-7.87 (m, 1H), 7.98-7.80 (m, 2H), 8.23-8.24 (m,1H), 8.80 (s, 1H).

Example 49N-(6-tert-Butylpyridin-3-yl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and starting materialsand heating the reaction mixture for 60 min.

MS: M+H=395.

Example 50N-(3-(Trifluoromethyl)phenethyl)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and starting materialsand heating the reaction mixture for 60 min.

MS: M+H=434.

Example 517-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(3-phenylpropyl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and starting materialsand heating the reaction mixture for 60 min.

MS: M+H=380.

Example 527-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(2-phenoxyethyl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 39 and using the appropriate reagents and starting materialsand heating the reaction mixture for 60 min.

MS: M+H=382.

Example 537-(Cyclohexylmethyl)-5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine

Diisopropylethyl amine(258 mg, 2 mmol) was added to the solution of5,6,7,8-tetrahydro-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine (55mg, 0.2 mmol) and (bromomethyl)cyclohexane (177 mg, 1 mmol) in ethanol(2 ML) and stirred at 80° C. for 48 h. Solvent was removed in vacuo, andthe residue was purified by column chromatography to yield the productas a light orange powder (7 mg, 9.5%).

MS: M+H=374.1. ¹H NMR DMSO-d₆ δ: 0.84-0.99 (m, 2H), 1.07-1.29 (m, 6H),1.58-1.69 (m, 5H), 1.75-1.78 (m, 2H), 2.29-2.31 (m, 2H), 3.43 (s, 2H),7.54-7.65 (m, 2H), 7.91-7.97 (m, 2H), 8.46 (s, 1H), 8.69 (d, J=2.4 Hz,1H), 8.85 (s, 1H), 9.12 (d, J=2.4 Hz, 1H).

Example 545,6,7,8-Tetrahydro-7-phenethyl-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 53 and using the appropriate reagents and startingmaterials.

MS: M+H=382.2. ¹H NMR DMSO-d₆ δ: 2.73-2.78 (m, 4H), 2.85-2.88 (m, 4H),3.57 (s, 2H), 7.19-7.21 (m, 1H), 7.27-7.30 (m, 4H), 7.55-7;58 (m, 1H),7.61-7.66 (m, 1H), 7.90-7.97 (m, 2H), 8.47 (s, 1H), 8.71 (d, J=2.2 Hz,1H), 8.87 (s, 1H), 9.13 (d, J=2.2 Hz, 1H).

Example 555,6,7,8-tetrahydro-7-(3-phenylpropyl)-N-(quinolin-3-yl)pyrido[3,4-d]pyrimidin-4-amine

The title compound was prepared following the procedure described abovefor Example 53 and using the appropriate reagents and startingmaterials.

MS: M+H=396.2. ¹H NMR DMSO-d₆ δ: 1.83-1.88 (m, 2H), 2.49-2.53 (m, 2H),2.62-2.66 (m, 2H), 2.76-2.77 (m, 4H), 3.48 (s, 2H), 7.16-7.31 (m, 5H),7.54-7.65 (m, 2H), 7.90-7.97 (m, 2H), 8.46 (s, 1H), 8.71 (d, J=2.4 Hz,1H), 8.87 (s, 1H), 9.13 (d, J=2.4 Hz, 1H).

Example 562-(4-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile

A mixture of4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(40 mg, 0.14 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (100 mg,0.63 mmol) (prepared according to the reference: Axton, C. A. et al, J.Chem. Soc. Perkin Trans. 1, 1992, 2203.), and acetonitrile (0.5 mL) washeated with microwave at 180° C. for 60 min. The solvent was removed invacuo and the residue was purified by chromatography to give a lightyellow solid (50 mg, 58%).

MS: M+H=405. ¹H NMR (DMSO-d6) δ 8.59 (s, 1H), 8.42 (s, 1H), 8.24 (dd,1H, J=4.8, 1.6 Hz), 7.86 (dd, 1H, J=8.0, 1.6 Hz), 7.74 (dd, 2H, J=6.8,2.0 Hz), 7.46 (dd, 2H, J=6.8, 2.0 Hz), 7.04 (dd, 1H, J=8.0, 4.4 Hz),4.36 (s, 2H), 3.68 (t, 2H, J=5.6 Hz), 2.81 (t, 2H, J=5.6 Hz), 1.68 (s,6H).

Example 574-(4-(Trifluoromethyl)phenylamino)-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-ol

Sodium hydrid (40 mg, 1 mmol, 60%) was added to the solution of2-(methansulphonyl)ethanol (124 mg, 1 mmol) in DMF (5 mL, anhydrous) andstirred at room temperature for 10 min. This solution (0.6 mL) was addedto the solution of7-(3-chloropyridin-2-yl)-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-4-amine(50 mg, 0.1 mmol) in DMF (1 mL) and was irradiated in microwave at 150°C. for 20 min. Solvent was removed in vacuo and the residue was purifiedby column chromatography to yield the product as a light brown solid (5mg, 12%).

MS: M+H=422.4. ¹H NMR DMSO-d₆ δ: 2.62 (t, J=5.6 Hz, 2H), 3.62 (t, J=5.6Hz, 2H), 4.19 (s, 2H), 7.04-7.07 (m, 1H), 7.67-7.71 (m, 2H), 7.86-7.88(m, 1H), 8.03-8.05 (m, 2H), 8.23-8.25 (m, 1H), 8.71 (s, 1H), 11.01 (s,1H).

Example 587-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-4,4-dimethylisoquinoline-1,3(2H,4H)-dione

A mixture of4-chloro-7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine(7.5 mg), 7-amino-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (30 mg)(prepared according to the reference: Snow, R. J. et al, J. Med. Chem.2002, 45, 3394), and acetonitrile (0.5 mL) was heated with microwave at180° C. for 60 min. The solvent was removed and the residue was purifiedby chromatography to give an off-white solid (6 mg).

MS:M+H=449 ¹H NMR (DMSO-d6) δ 11.31 (s, 1H), 8.77 (s, 1H), 8.46 (s, 1H),8.39 (s, 1H), 8.25 (d, 1H, J=4.8 Hz), 8.10 (d, 1H, J=8.0 Hz), 7.87 (d,1H, J=8.0 Hz), 7.64 (d, 1H, J=8.0 Hz), 7.04 (dd, 1H, J=8.0, 4.8 Hz),4.37 (s, 2H), 3.70 (s, 2H), 2.84 (s, 2H), 1.52 (s, 6H).

Example 59 A.1-(3,4-Dihydro-4,4-dimethyl-7-nitroquinolin-1(2H)-yl)ethanone

To a stirred solution of1,2,3,4-tetrahydro-4,4-dimethyl-7-nitroquinoline (Rami et al, WO03/068749) (500 mg, 2.42 mmol), DMAP (5 mg) in pyridine (2 mL) was addedacetic anhydride (0.46 mL, 4.9 mmol). The mixture was stirred at roomtemperature for 10 h, and then heated at 60° C. for 5 h. After cooling,the mixture was treated with water and extracted with EtOAc. Thecombined organic layers were washed with sat. aq. NaHCO₃, 1N HCl, brine,dried, and evaporated. The residue was purified by chromatography togive a light yellow solid (550 mg, 92%).

MS: M+H=249.

B. 1-(7-Amino-3,4-dihydro-4,4-dimethylquinolin-1(2H)-yl)ethanone

A mixture of the nitro compound (530 mg, 2.14 mmol), 10% Pd—C (30 mg),MeOH (10 mL) was stirred at H₂ atmosphere (1 atm) for 2 h. The mixturewas filtered and the filtrate was evaporated under reduced pressure. Theresidue was purified by chromatography to give a light yellow solid (380mg, 82%).

MS: M+H=219.

C.1-(7-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylquinolin-1(2H)-yl)ethanone

A mixture of the chloride (20 mg, 0.071 mmol),1-(7-amino-3,4-dihydro-4,4-dimethylquinolin-1(2H)-yl)ethanone (40 mg,0.18 mmol), and acetonitrile (0.5 mL) was heated with microwave at 180°C. for 60 min. The mixture was diluted with EtOAc (50 mL), washed withaq. NaHCO₃, brine, dried, and concentrated. The residue was purified bychromatography to give the product (15 mg).

MS: M+H=463.

D.7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethylquinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine

A mixture of1-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylquinolin-1(2H)-yl)ethanone(10 mg), acetonitrile (2 mL), and 5 N HCl (0.5 mL) was heated at 90° C.for 3 h. The cooled solution was treated with sat. aq. NaHCO₃, extractedwith EtOAc (15 mL×3). The combined organic layers were washed withbrine, dried, and evaporated. The residue was purified by TLC to give anoff-white solid (7 mg).

MS: M+H=421. ¹H NMR (DMSO-d6) δ 8.33 (s, 1H), 8.24 (dd, 1H, J=4.8, 1.6Hz), 8.14 (s, 1H), 7.85 (dd, 1H, J=8.0, 1.6 Hz), 7.03 (dd, 1H, J=7.6,4.8 Hz), 7.01 (d, 1H, J=8.0 Hz), 6.78 (d, 1H, J=1.6 Hz), 6.68 (dd, 1H,J=8.4, 2.0 Hz), 5.70 (s, 1H), 4.32 (s, 2H), 3.66 (t, 2H, J=5.6 Hz), 3.17(m, 2H), 2.75 (t, 2H, J=5.6 Hz), 1.60 (t, 2H, J=5.6 Hz), 1.19 (s, 6H).

Example 607-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-1,4,4-trimethylquinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine

A mixture of the chloride (15 mg, 0.053 mmol),1,2,3,4-tetrahydro-1,4,4-trimethylquinolin-7-amine (30 mg, 0.16 mmol),and acetonitrile (0.5 mL) was heated with microwave at 180° C. for 60min. The mixture was diluted with EtOAc (50 mL), washed with aq. NaHCO₃,brine, dried, and concentrated. The residue was purified by TLC to givethe product as an off-white foam.

MS: M+H=435. ¹H NMR (DMSO-d6) δ 8.35 (s, 1H), 8.24 (dd, 1H, J=4.8, 1.6Hz), 8.21 (s, 1H), 7.85 (dd, 1H, J=7.6, 1.6 Hz), 7.07 (d, 1H, J=8.4 Hz),7.03 (dd, 1H, J=7.6, 4.8 Hz), 6.99 (dd, 1H, J=8.4, 2.4 Hz), 6.84 (d, 1H,J=1.6 Hz), 4.33 (s, 2H), 3.67 (t, 2H, J=5.6 Hz), 3.18 (t, 2H, J=6.0 Hz),2.82 (s, 3H), 2.77 (t, 2H, J=5.6 Hz), 1.70 (t, 2H,11J=5.6 Hz), 1.22 (s,6H).

Example 611-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylisoquinolin-2(1H)-yl)ethanone

A. 1,2,3,4-Tetrahydro-4,4-dimethylisoquinolin-7-amine

To a stirred mixture of LiAlH₄ (800 mg, 21 mmol) and anhydrous THF (30mL) was added at 0° C. a solution of7-amino-4,4-dimethylisoquinoline-1,3(2H,4H)-dione (500 mg, 2.5 mmol) inTHF (5 mL). The mixture was stirred at room temperature under N₂ for 24h, and then carefully treated with wet THF, 10% aq. NaOH, and filteredthrough Celite. The filtrate was concentrated and the residue wasdissolved in EtOAc (150 mL). The organic phase was washed with brine,dried (Na₂SO₄), and evaporated. The residue was purified bychromatography to give the title compound (270 mg, 63%).

MS: M+H=177.

B. 1-(7-Amino-3,4-dihydro-4,4-dimethylisoquinolin-2(1H)-yl)ethanone

To a stirred solution of1,2,3,4-tetrahydro-4,4-dimethylisoquinolin-7-amine (200 mg, 1.14 mmol)and Et₃N (0.12 mL) in CH₂Cl₂ (10 mL) at −15° C. was added a solution ofa anhydride (70 μL) in CH₂Cl₂ (1 mL). The mixture was stirred at −15° C.for 30 min, and then slowly warmed to room temperature and stirredovernight. The mixture was diluted with CH₂Cl₂ (50 mL), washed with sat.aq. NaHCO₃, brine, dried, and concentrated. The residue was purified bychromatography to give the product as a foam.

MS: M+H=219. ¹H NMR (DMSO-d6) δ 7.00 (m, 1H), 6.43 (m, 1H), 6.26 (s,1H), 4.88 and 4.90 (s, 2H), 4.51 and 4.45 (s, 2H), 3.38 and 3.37 (s,2H), 2.09 and 2.05 (s, 3H), 1.16 and 1.10 (s, 6H).

C.1-(7-(7-(3-Chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylisoquinolin-2(1H)-yl)ethanone

A mixture of the chloride (35 mg, 0.12 mmol),1-(7-amino-3,4-dihydro-4,4-dimethylisoquinolin-2(1H)-yl)ethanone (80 mg,0.37 mmol), and acetonitrile (1.5 mL) was heated with microwave at 180°C. for 60 min. The mixture was treated with aq. Na₂CO₃ solution, andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine, dried, and evaporated. The residue was purified by TLC togive the product as a light yellow solid (18 mg).

MS: M+H=463. ¹H NMR (DMSO-d6) δ 8.45 and 8.44 (s, 1H), 8.40 and 8.39 (s,1H), 8.24 (m, 1H), 7.88-7.84 (m, 1H), 7.53-7.43 (m, 2H), 7.33 (m, 1H),7.04 (m, 1H), 4.67 and 4.61 (s, 2H), 4.34 (s, 2H), 3.68 (t, 2H, J=5.6Hz), 3.47 (s, 2H), 2.79 (m, 2H), 2.13 and 2.09 (s, 3H), 1.25 and 1.19(s, 6H).

Example 627-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydro-N-(1,2,3,4-tetrahydro-4,4-dimethylisoquinolin-7-yl)pyrido[3,4-d]pyrimidin-4-amine

A mixture of1-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylisoquinolin-2(1H)-yl)ethanone(10 mg), acetonitrile (2 mL), and 5 N HCl (0.5 mL) was heated overnightat 90° C. The cooled solution was treated with aq. Na₂CO₃, extractedwith EtOAc (15 mL×3). The combined organic layers were washed withbrine, dried, and evaporated. The residue was purified by TLC to give alight yellow solid (5 mg).

MS: M+H=421. ¹H NMR (DMSO-d6) δ 8.42-8.36 (m, 2H), 8.24 (dd, 1H, J=4.4,1.6 Hz), 7.86 (dd, 1H, J=8.0, 1.6 Hz), 7.45 (m, 1H), 7.32 (m, 2H), 7.03(m, 1H), 4.34 (s, 2H), 3.92 and 3.63 (s, 2H), 3.67 (t, 2H, J=5.6 Hz),2.82 and 2.57 (s, 2H), 2.78 (t, 2H, J=5.6 Hz), 1.26 and 1.24 (s, 6H).

In addition to the amine compounds exemplified above, the followingcompounds recited below, which comprise various substituted amines ofthis invention, can be prepared using the procedure and syntheticschemes described above, or some modification their of, and thecorresponding starting materials, appropriate reagents, and purificationmethods known to those skilled in the art.

The following biological examples, Examples 63-67, are offered toillustrate the present invention and are not to be construed in any wayas limiting its scope. In the examples below, all temperatures are indegrees Celsius (unless otherwise indicated).

Example 63 High Throughput Screening of VR1 Antagonists forDetermination of in vitro Efficacy using a Calcium Imaging Assay

VR1 protein is a heat-gated cation channel that exchanges about 10calcium ions for every sodium ion resulting in neuronal membranedepolarization and elevated intracellular calcium ion levels. Thereforethe functional activity of compounds at the VR1 receptor may bedetermined by measuring changes in intracellular calcium levels in 293cells expressing capsaicin-insensitive VR1 receptor variants. A dualwavelength ratiometric dye, Fura2, was used as an indicator of relativelevels of calcium ions in a 96 well format using a bench top scanningfluorometer with integrated fluidics and temperature control (FlexStation, Molecular Devices).

A dual wavelength ratiometric dye, Fura2, was used as an indicator ofrelative levels of [Ca2+] in a 96 well format using a bench top scanningfluorometer with integrated fluidics and temperature control (FlexStation, Molecular Devices).

HEK 293 cells expressing hVR1 were grown on PDL coated 96-wellblack-walled plates, in the presence of a DMEM medium containing 5%Penstrep, 5% Glutamax, 200 ug/mL Hygromycin, 5 μg/mL Blasticide and 10%heat inactivated FBS. Prior to assay, the cells were loaded with 5 μg/mLFura2 in normal saline solution at 37° C. for 40 minutes. Cells werethen washed with normal saline to remove the dye.

The assay consists of two stages; a pre-treatment phase followed by atreatment phase. In the pretreatment phase, 50 μl of a compound solutionwas added to the cells. Immediately following, 50 μl of the testcompound in the presence of agonist (a saline solution plus 10 mM citricacid bufferd to pH 5.7 with HCl) was added. Fura2 was excited at 340 and380 nM to indicate relative calcium concentration. Changes in wavelengthmeasurements were made throughout the course of the experiment in 4second intervals over a period of 3 minutes. The fluorescence ratio fromthe excitations at 340 nM and 380 nM was recorded for analysis.Responses were measured as peak fluorescence ratio aftercompound-agonist addition minus baseline fluorescence ratio prior totreatment and were calculated for each concentration tested using theSoftMaxPro software. Data was expressed as percentage inhibitioncalculated as follows:

${{Percentage}\mspace{14mu}{Inhibition}} = {1 - {\frac{\begin{matrix}{\left( {{Response}\mspace{14mu}{of}\mspace{14mu}{Compound}\mspace{14mu}{with}\mspace{14mu}{Agonist}} \right) -} \\\left( {{Response}\mspace{14mu}{of}\mspace{14mu}{saline}\mspace{14mu}{Control}} \right)\end{matrix}}{\left( {{{Response}\mspace{14mu}{of}\mspace{14mu}{Agonist}} - {{Response}\mspace{14mu}{of}\mspace{14mu}{saline}\mspace{14mu}{Control}}} \right)} \times 100}}$

To establish the IC₅₀ of each compound, compounds were tested atconcentrations ranging from 10 nM to 3.3 μM. A dose response curve wasthen determined, from which the IC₅₀ of each compound was calculated.

The relative strengths of the percentage inhibition values and thecorresponding IC₅₀s are set forth in Table 1, below.

TABLE 1 % Inhibition ID STRUCTURE MW @ 1 μM IC₅₀ (nM) 1

405.8 ++++ *** 2

372.5 IA NT 3

393.9 ++++ **** 4

427.5 ++++ **** 5

438.0 ++++ **** 6

471.5 ++++ **** 7

380.4 IA NT 8

437.6 ++++ *** 9

449.5 ++++ *** 10

463.5 +++ *** 11

389.4 ++++ *** 12

439.4 ++++ * 13

493.1 ++ NT 14

447.5 + NT 15

403.8 IA * 16

477.5 IA * 17

420.8 ++++ NT 18

337.8 ++ NT 19

355.8 +++ NT 20

406.8 + NT 21

450.4 +++ NT 22

469.9 IA NT 23

513.5 + NT 24

451.9 NT *** 25

483.9 IA NT 26

404.8 + NT 27

435.8 NT *** 28

440.0 ++++ **** 29

423.9 ++++ **** 30

374.4 IA NT 31

428.5 IA NT 32

492.0 IA NT 33

534.0 + NT 34

448.9 + *** 35

449.9 ++++ NT 36

374.4 ++ ** 37

430.8 ++++ NT 38

367.5 IA *** 39

365.9 ++++ *** 40

400.3 +++ * 41

386.3 ++ *** 42

406.7 ++ NT 43

405.8 IA NT 44

370.4 IA NT 45

384.4 IA NT 46

384.4 + NT 47

384.4 IA NT 48

449.9 ++++ *** 49

394.9 ++++ NT 50

433.9 + NT 51

379.9 + NT 52

381.9 + NT 53

373.5 NT NT 54

381.5 NT NT 55

395.5 NT NT 56

404.9 ++++ **** 57

421.8 + * 58

448.9 NT * 59

420.9 NT *** 60

435.0 NT **** 61

463.0 NT * 62

420.9 NT * For purposes of Table 1, the activity of each compound isexpressed as follows: “+” compound exhibited 0-25% inhibition of calciumion influx induced by capsaicin stimulation. “++” compound exhibited26-50% inhibition of calcium ion influx induced by capsaicinstimulation. “+++” compound exhibited 51-75% inhibition of calcium ioninflux induced by capsaicin stimulation. “++++” compound exhibited 76%or greater inhibition of calcium ion influx induced by capsaicinstimulation. “****” compound exhibited IC₅₀ values of <100 nM. “***”compound exhibited IC₅₀ values of 101-500 nM. “**” compound exhibitedIC₅₀ values of 501-1000 nM. “*” compound exhibited IC₅₀ values of >1000nM. IA inactive. NT Not tested in this model. It should be notedhowever, that the compounds were tested in capsaicin binding assays, andthat activity consistent with the stated utility of the compounds of theinvention, was observed.

Example 64 Two-Electrode Voltage Clamp Recording using the Opus Express(Axon Instruments/Molecular Devices Corporation)

Oocyte Preparation

Xenopus ovaries obtained from NASCO were isolated by enzymaticdissociation using collagenase (Worthington, 2 mg/ml). Oocytes were thenindividually injected with HsVR1 RNA (0.5 μg/μl). Injected oocytes arestored in standard oocyte incubation solution, ND96, containing 96 mMNaCl, 2 mM KCl, 1 mM MgCl₂, 0.3 mM CaCl₂ and 50 μg/ml Gentamicin at 16°C. Capsaicin induced VR1 current is observed in oocytes 4-5 days afterinjection.

Eight oocytes are placed in the recording chambers. Each oocyte isimpaled by 2 glass electrodes having resistances of 0.5 to 1 MOhm whenfilled with a 3 M KCl solution. Electrode advancement and oocyteimpalement are under software control (OpusXpress 1.1, AxonInstruments).

VR1 expression in the oocytes is verified using 250 nM capsaicin. Testsolution delivery to the oocytes during the experiment is also undersoftware control. The solutions are prepared in 96 well plates androbotically pipetted into the oocyte recording chambers by an 8 channelpipetter.

Oocytes are exposed to several 250 μl applications of 250 nM capsaicinuntil a stable current amplitude is obtained with each application.

A set of 96 well plates containing the test solutions is prepared sothat the sequence of solution application to the oocyte is as follows:250 μls of 250 nM capsaicin is followed by a several minute wash withstandard oocyte saline. 1 ml of the test compound is then added at aparticular test concentration, followed immediately by 250 μl of thecompound at the same concentration plus 250 nM capsaicin.

The capsaicin induced VR1 current is recorded in the presence andabsence of test compound for each concentration. The standard testconcentrations range from 0.3 to 2000 nM.

Quantitative measurement of VR1 current block was carried out bycalculating the area under the curve described by the inward current.The resulting numbers for capsaicin induced currents in the presence ofincreasing compound concentration are normalized to the maximum currentobtained. These points are then plotted on a logarithmic scale andfitted by a Hill function. The IC₅₀ values for each compound tested werethen calculated from the resulting Hill fit.

All compounds that inhibited capsaicin induced current greater than 50%were considered positives. The data obtained for compounds tested inthis assay are set forth in Table 2, below. The IC₅₀ dose response datafor Compound 1 are also presented in FIG. 1.

TABLE 2 Compound EPHYS ID MW IC₅₀, nM 1 405.81 *** 3 393.92 **** 5437.97 **** 8 437.57 *** 9 449.46 *** 10 463.48 *** 26 404.82 * 28440.01 **** 29 423.95 **** 33 533.98 ** 34 448.88 ** 35 449.86 *** 37430.82 *** 39 365.87 * 46 384.40 ** 48 449.86 **** For purposes of Table2, the activity of each compound is expressed as follows: “****”compound exhibited IC₅₀ values of <100 nM. “***” compound exhibited IC₅₀values of 101-500 nM. “**” compound exhibited IC₅₀ values of 501-1000nM. “*” compound exhibited IC₅₀ values of >1000 nM.

Example 65 Thermal Hyperalgesia

Sprague-Dawley male rats obtained from Charles River, San Diego, Calif.were purchased at 150-175 g, and held for at least one week beforetesting. Pain was induced by injecting 100 μl of 2% carrageenan in 0.9%saline sub-Q into the right ventral hindpaw while the animals were underisofluorane anesthesia. Animals were then dosed one hour after with aconcentration of 30 mg/kg of Compound 1. Two hours later, afteracclimatizing in testing chambers for 20-30 minutes, animals were testedon both hindpaws for latency of paw withdrawal using a thermal testingapparatus. 2-3 trials were conducted with 10 minutes between trials. Asdemonstrated in FIG. 2, a dose of Compound 1 at 30 mg/kg significantlyincreased latency of paw withdrawal demonstrating reversal of thermalhyperalagesia. The figure depicts the time in seconds until animalswithdraw from thermal stimulation at baseline and two hours afteradministration of delivery vehicle, control compound, and the dose of 30mg/kg of Compound 1.

Example 66 Pharmacokinetic Profile

The pharmacokinetic profile of Compound 1 was evaluated followingintravenous and oral administration in rats. Sprague-Dawley male ratsobtained from Charles River, San Diego, Calif. were acclimated for 24hours.

Compounds of this invention were formulated at a concentration of 0.5mg/mL for IV administration at a 1 mg/kg dose and 1 mg/mL for oraladministration at a 5 mg/kg dose. All animals were weighed beforedosing. The body weight was used to calculate the actual dose for eachanimal. The intravenous dose was administered through the jugular veincatheter in less than 1 minute. The oral dose volume was 1.5 mL for allPO rats administered through oral lavage.

For IV dosing, blood samples were collected using a pre-heparinizedsyringe via the caproic artery catheter before dosing and at t=2, 5, 15,30, 60, 120, 180, 360, and 480 minutes post dosing. For PO dosing, bloodsamples were collected using a pre-heparinized syringe via the caproicartery catheter before dosing and at t=5, 15, 30, 60, 120, 180, 360, and480 minutes post dosing. 250 uL of blood was obtained at each time pointfrom each animal. Equal volumes of 0.9% normal saline were replaced toprevent dehydration. The whole blood samples were maintained on iceuntil centrifugation. Blood samples were centrifuged at 14,000 rpm for10 minutes at 4° C., and the upper plasma layer was transferred into aclean vial and store at −80° C.

The plasma was analyzed. The rat PK properties are set forth in Table 3,below.

TABLE 3 Com- pound Cmax Tmax F Vd Cls T/2 ID MW (ng/mL) (hr) (%) (L/Kg)(L/hrKg) (hr) 1 405.81 1379 1.01 37 1.28 0.34 2.52 9 449.46 156 1.6747.9 13 1.99 4.37 18 337.81 44.58 0.92 4.07 18 4.45 2.55 19 355.80 24.50.68 5.66 12.2 4.47 1.9 37 430.82 49.43 3.33 17.9 12.4 4.02 2.15

Example 67 Analysis of Plasma Protein Binding

Membranes from Harvard/Amika with a molecular weight cutoff of 5,000were rinsed with dH₂O then placed in pH 7.4 PBS supplied by Gibco. Themembranes were allowed to soak for 1 hour. A stock of the test articlewas pooled with Warfarin, Atropine at 2 mM in DMSO. The test article wasthen dosed into human plasma in sodium citrate, Rat Plasma, and MousePlasma to a final 10 μM concentration (0.5% DMSO v/v).

The pre-soaked membranes were then placed into dialysis chambers. 500 μLof PBS was added to one side of the chamber, and 500 μL of the Matrixcontaining the test article was added to the other side of the chamber.The chambers were then placed into an enclosed, heated rocker, which waspre-warmed to 37° C. and allowed to reach equilibrium for at least 22hours. After 22 hours both sides were sampled. 100 μL of the donor sidewas added to 500 μL of PBS. 100 μL of the PBS side was added to 20 μL offresh matrix. Samples then were crashed with 1:1 Acetonitrile andcentrifuged at 10,000 RPM for 10 minutes. 100 μL of supernatant wasplaced into LC/MS vials for analysis.

Standards were prepared in a 1:5 plasma:PBS mixture at 5, 1.5, 0.5,0.15, 0.05, 0.015 and 0.005 μM concentrations. The samples and standardswere placed into HPLC vials and assayed by LC/MS. Protein binding valueswere calculated as follows:% Bound=[(Concentration in Donor−Concentration inReceiver)/(Concentration in Donor)]×100.% Recovery=[(Concentration in donor+Concentration inReceiver)]/(Concentration in Normal Initial)]×100

From the above, Compound 1 demonstrated rat and human plasma proteinbinding of more than 99.9%.

From the foregoing description, various modifications and changes in thecompositions and methods of this invention will occur to those skilledin the art. All such modifications coming within the scope of theappended claims are intended to be included therein.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

1. A method for ameliorating or delaying the onset of a disease orcondition in a mammal, which comprises administering to the mammal aneffective disease- or condition-ameliorating, or onset-delaying amountof a pharmaceutical composition, wherein said pharmaceutical compositioncomprises a pharmaceutically acceptable carrier and a pharmaceuticallyeffective amount of a compound, said compound having a formula:

wherein A, B and Y are CR^(2′)R^(2′); W is N; and Z is CR⁴; R¹ isselected from phenyl, unsubstituted or substituted with alkyl,substituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted sulfone, substituted or unsubstituted aminosulfonyl,cyano, and halo; or R¹ is selected from substituted or unsubstitutedpyridyl, substituted or unsubstituted indolyl, substituted orunsubstituted benzimidazolyl, substituted or unsubstituted indazolyl,substituted or unsubstituted tetrahydroquinoline, and substituted orunsubstituted tetrahydroisoquinoline; R² is H; and each R^(2′) isindependently selected from hydrogen, substituted or unsubstituted C₁-C₆alkyl; R³ is selected from substituted or unsubstituted phenyl; or R³ is2-pyridyl substituted with alkoxy, sulfonyl, or sulfonamidyl; R⁴ isselected from H, alkyl, substituted alkyl, acyl, substituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl,substituted or unsubstituted benzylamino, benzyloxy, substitutedbenzyloxy, amino, benzyl, substituted or unsubstituted sulfoxide,substituted or unsubstituted sulfone, substituted or unsubstitutedsulfanyl, substituted or unsubstituted aminosulfonyl, substituted orunsubstituted dihydroxyphosphoryl, substituted or unsubstitutedaminodihydroxyphosphoryl, azido, carboxy, substituted or unsubstitutedcarbamoyl, cyano, substituted or unsubstituted cycloalkyl, substitutedor unsubstituted cycloheteroalkyl, substituted or unsubstituteddialkylamino, halo, hydroxy, nitro, and thiol; or a pharmaceuticallyacceptable salt, or stereoisomers or tautomers thereof; wherein thedisease or condition is selected from inflammatory pain, neuropathicpain, osteoarthritis, overactive bladder, migraine and dental pain. 2.The method of claim 1, wherein the disease or condition is inflammatorypain.
 3. The method of claim 1, wherein the disease or condition isneuropathic pain.
 4. The method of claim 1, wherein the disease orcondition is osteoarthritis.
 5. The method of claim 1, wherein thedisease or condition is overactive bladder.
 6. The method of claim 1,wherein the disease or condition is migraine.
 7. The method of claim 1,wherein the disease or condition is dental pain.